AU2007229850A1 - Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use - Google Patents

Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use Download PDF

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AU2007229850A1
AU2007229850A1 AU2007229850A AU2007229850A AU2007229850A1 AU 2007229850 A1 AU2007229850 A1 AU 2007229850A1 AU 2007229850 A AU2007229850 A AU 2007229850A AU 2007229850 A AU2007229850 A AU 2007229850A AU 2007229850 A1 AU2007229850 A1 AU 2007229850A1
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Australia
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pct
groups
compound
mmol
aryl
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AU2007229850A
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Jiang Chang
Ronald M. Kim
Ashley Rouse Lins
Emma R. Parmee
Qiang Tan
Cangming Yang
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Merck and Co Inc
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Merck and Co Inc
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    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
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    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
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    • C07D277/62—Benzothiazoles
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    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
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    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
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    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/12—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 3 and unsubstituted in position 7
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    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
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    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
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    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
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    • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms

Description

WO 2007/111864 PCT/US2007/006806 TITLE OF THE INVENTION GLUCAGON RECEPTOR ANTAGONIST COMPOUNDS, COMPOSITIONS CONTAINING SUCH COMPOUNDS AND METHODS OF USE 5 BACKGROUND OF THE INVENTION The present invention relates to glucagon receptor antagonist compounds, compositions containing such compounds and various methods of treatment relating to type 2 diabetes mellitus and related conditions. Diabetes refers to a disease process derived from multiple causative factors and is ) characterized by elevated levels of plasma glucose (hyperglycemia) in the fasting state or following glucose administration during an oral glucose tolerance test. Frank diabetes mellitus (e.g., a blood glucose level >126 mg/dL in a fasting state) is associated with increased and premature cardiovascular morbidity and mortality, and is related directly and indirectly to various metabolic conditions, including alterations of lipid, lipoprotein and apolipoprotein metabolism. 5 Patients with non-insulin dependent diabetes mellitus (type 2 diabetes mellitus), approximately 95% of patients with diabetes mellitus, frequently display elevated levels of serum lipids, such as cholesterol and triglycerides, and have poor blood-lipid profiles, with high levels of LDL cholesterol and low levels of HDL-cholesterol. Those suffering from Type 2 diabetes mellitus are thus at an increased risk of developing macrovascular and microvascular complications, including coronary heart ) disease, stroke, peripheral vascular disease, hypertension (for example, blood pressure > 130/80 mmHg in a resting state), nephropathy, neuropathy and retinopathy. Patients having type 2 diabetes mellitus characteristically exhibit elevated plasma insulin levels compared with nondiabetic patients; these patients have developed a resistance to insulin stimulation of glucose and lipid metabolism in the main insulin-sensitive tissues (muscle, liver and adipose tissues). Thus, Type 2 diabetes, at least early in the natural progression of the disease is characterized primarily by insulin resistance rather than by a decrease in insulin production, resulting in insufficient uptake, oxidation and storage of glucose in muscle, inadequate repression of lipolysis in adipose tissue, and excess glucose production and secretion by the liver. The net effect of decreased sensitivity to insulin is high levels of insulin circulating in the blood without appropriate reduction in S plasma glucose (hyperglycemia). Hyperinsulinemia is a risk factor for developing hypertension and may also contribute to vascular disease. Glucagon serves as the major regulatory hormone attenuating the effect of insulin in its inhibition of liver gluconeogenesis and is normally secreted by alpha cells in pancreatic islets in response to falling blood glucose levels. The hormone binds to specific receptors in liver cells that triggers glycogenolysis and an increase in gluconeogenesis through cAMP-mediated events. These responses generate glucose (e.g. hepatic glucose production) to help maintain euglycemia by preventing blood glucose levels from falling significantly. In addition to elevated levels of circulating insulin, type 2 diabetics have elevated levels of plasma glucagon and increased rates of hepatic glucose production. -1- WO 2007/111864 PCT/US2007/006806 Antagonists of the glucagon receptor are useful in improving insulin responsiveness in the liver, decreasing the rate of gluconeogenesis and glycogenolysis, and lowering the rate of hepatic glucose output resulting in a decrease in the levels of plasma glucose. SUMMARY OF THE INVENTION The present invention is directed to a compound represented by formula 1: (R")2 )n A
(R
3
)
4 (R2) Rb C(O)NHRa or a pharmaceutically acceptable salt or solvate thereof, wherein: Ring A represents a 6-10 membered Aryl group or a 5-10 membered heteroaryl or ) partially aromatic heterocyclic group containing 1-4 heteroatoms, 0-4 of which are N atoms, and 0-1 of which are O or S atoms; two R' and two R 2 groups are present and represent hydrogen, or one or two R' and R groups are selected from (a), (b) and (c) below: 5 (a) halo, OH, CO 2
R
4 , SOpR 5 , CN, NO 2
C(O)NRR
7 or NR 6
R
7 ; (b) CI-joalkyl, C(O)CI-loalkyl, OCi-6alkyl, C 2 4 6alkenyl, the alkyl portions being optionally substituted with: (1) 1-5 halo groups, up to perhalo, and 1-2 OH groups; (c) a 6-10 membered Aryl, O-Aryl or S-Aryl group, or a 5-10 membered HAR, O-HAR or S HAR group containing 0-4 nitrogen and 0-10 or S atoms, said group being optionally substituted with 1 0 3 groups selected from (a) and (b) above, or two R groups can be taken together in combination and represent a methylene or ethylene bridge forming a carbocyclic ring containing 5 or 6 atoms, or a fused phenyl ring optionally substituted with 1-3 halo groups and 1-2 CN, SOpR 5 , C 1
.
3 alkyl, C 1
.
3 alkoxy, haloC 1
.
3 alkyl, haloC.
3 alkoxy 5 groups, and the R' groups represent H or are selected from (a) through (c) above; four R 3 groups are present as follows: 1) 0-1 R 3 group is selected from the group consisting of: Aryl, HAR, 0 -(CH 2
)
1 -4Aryl, -(CH 2
)
1 -4HAR, -X-Aryl, -X-HAR, -X-C 1
.
4 Alkyl-Aryl and -X- C 1 .4Alkyl-HAR; wherein X represents O, S, S(0) or S(O)2 ; -2- WO 2007/111864 PCT/US2007/006806 said Aryl and HAR groups and portions of the groups above being optionally substituted with 1-4 halo atoms, and 1-2 members selected from: OH, CN, C 1 _6alkyl, OCz.6alkyl, haloC.
6 alkyl, OCi-6haloalkyl, NO 2 , SOpR 5 , C 2 -6alkenyl, OC 2 6alkenyl, NR 6
R
7 and HAR; 2) 0-3 R? groups are selected from: OH, CN, oxo, NO 2 , SOpR, NR 6
R
7 , Ci. toalkyl, haloC- 1 oalkyl, OCI-loalkyl, OCI-lo 10 haloalkyl, C 2 _10alkenyl, OC 2 .6alkenyl and haloC 2 4 alkenyl,and 3) the remaining R groups are H or halo atoms; R is H or C- 1
.
6 alkyl, and Ri represents a member selected from the group consisting of: C- 10 alkyl, Aryl or Ar-C. 4 alkyl; R and R 7 each independently represent H or C 1 -6alkyl; n represents an integer of from 0-5; p is 0, 1 or 2;
R
a represents CH 2
CH
2
CO
2
R
4 , CH 2
CH(OH)CO
2 Ror 5-tetrazolyl; and Rb is H or is selected from the group consisting of: halo, CN, NO 2 , OH, C 1 _3alkyl, OCI. 3 alkyl, haloC.
3 alkyl and haloCl- 3 alkoxy. DETAILED DESCRIPTION OF THE INVENTION The invention is described herein in detail using the terms defined below unless otherwise specified. "Alkyl", as well as other groups having the prefix "alk", such as alkoxy, alkanoyl and the like, means carbon chains which may be linear, branched, or cyclic, or combinations thereof, containing the indicated number of carbon atoms. If no number is specified, 1-10 carbon atoms are intended for linear or branched alkyl groups. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and the like. Cycloalkyl is a subset of alkyl; if no number of atoms is specified, 3-10 carbon atoms are intended, forming 1-3 carbocyclic rings that are ) fused. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decahydronaphthyl and the like. "Alkenyl" means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like. 5 "Alkynyl" means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-l-pentynyl, 2-heptynyl and the like. -3- WO 2007/111864 PCT/US2007/006806 "Aryl" (Ar) means mono- and bicyclic aromatic rings containing 6-12 carbon atoms. Examples of aryl include phenyl, naphthyl, indenyl and the like. "Aryl" also includes monocyclic rings fused to an aryl group. Examples include tetrahydronaphthyl, indanyl and the like. "Heteroaryl" (HAR) means a mono- or bicyclic aromatic ring or ring system containing at least one heteroatom selected from O, S and N, with each ring containing 5 to 6 atoms. Examples include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl and the like. Heteroaryl also includes aromatic heterocyclic groups fused to heterocycles that are non-aromatic or partially aromatic, and aromatic heterocyclic groups fused to cycloalkyl rings. Heteroaryl also includes such groups in charged form, e.g., pyridinium. "Heterocyclyl" (Hetcy) means mono- and bicyclic saturated rings and ring systems containing at least one heteroatom selected from N, S and 0, each of said ring having from 3 to 10 atoms in which the point of attachment may be carbon or nitrogen. Examples of "heterocyclyl" include pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, 2,3-dihydrofuro(2,3-b)pyridyl, benzoxazinyl, tetrahydrohydroquinolinyl, tetrahydroisoquinolinyl, dihydroindolyl, and the like The term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2- or 4-pyridones attached through the nitrogen or N-substituted-(1H, 3H)-pyrimidine-2, 4-diones (N-substituted uracils). Heterocyclyl moreover includes such moieties in charged form, e.g., piperidinium. )"Halogen" (Halo) includes fluorine, chlorine, bromine and iodine. One aspect of the present invention is directed to a compound represented by formula I: (R) )n A (R 3
)
4 2 Rb 1 C(0)NHRa or a pharmaceutically acceptable salt or solvate thereof, wherein: 5 Ring A represents a 6-10 membered Aryl group or a 5-10 membered heteroaryl or partially aromatic heterocyclic group containing 1-4 heteroatoms, 0-4 of which are N atoms, and 0-1 of which are O or S atoms; two R' and two R 2 groups are present and represent hydrogen, or one or two R and R 2 0 groups are selected from (a), (b) and (c) below: (a) halo, OH, CO 2
R
4 , SOPR 5 , CN, NO 2
C(O)NRR
7 or NR 6
R
7 ; -4- WO 2007/111864 PCT/US2007/006806 (b)
C-
1 oalkyl, C(O)C 1 .10alkyl, OC 1 6alkyl, C 2 .alkenyl, the alkyl portions being optionally substituted with: (1) 1-5 halo groups, up to perhalo, and 1-2 OH groups; (c) a 6-10 membered Aryl, O-Aryl or S-Aryl group, or a 5-10 membered HAR, O-HAR or S HIAR group containing 0-4 nitrogen and 0-10 or S atoms, said group being optionally substituted with 1 3 groups selected from (a) and (b) above, or two R2 groups can be taken together in combination and represent a methylene or ethylene bridge forming a carbocyclic ring containing 5 or 6 atoms, or a fused phenyl ring optionally substituted with 1-3 halo groups and 1-2 CN, SOpR 5 , CI.
3 alkyl, C 1
-
3 alkoxy, haloCI-.
3 alkyl, haloCl_ 3 alkoxy groups, and the R' groups represent H or are selected from (a) through (c) above; four R 3 groups are present as follows: 2) 0-1 R3 group is selected from the group consisting of: Aryl, HAR, 5 -(CH 2
)
1 4Aryl, -(CH 2
)
1 I4HAR, -X-Aryl, -X-HAR, -X-C14Alkyl-Aryl and -X- C 14 Alkyl-HAR; wherein X represents O, S, S(0) or S(0)2 ; said Aryl and HAR groups and portions of the groups above being optionally substituted with 1-4 halo atoms, and 1-2 members selected from: OH, CN, CI-6alkyI, OC 4 6alkyl, haloCi 6 alkyl, OC 1 -haloalkyl, NO 2 , SOpR 5 , C2-6alkenyl, OC 2 -6alkenyl, NR 6
R
7 and HAR; 0 2) 0-3 R3 groups are selected from: OH, CN, oxo, NO 2 , SOpR s , NR 6
R
7 , C'. 1 oalkyl, haloC-Ioalkyl, OCI-l.
1 0 alkyl, OCI- 10 haloalkyl, C 2
-
1 oalkenyl, OC 2 -6alkenyl and haloC 2 -4alkenyl,and 5 3) the remaining R3 groups are H or halo atoms; R4 is H or CI_6alkyl, and
R
s represents a member selected from the group consisting of: Cl.
1 oalkyl, Aryl or Ar-C. 4 alkyl; 0 R6 and R each independently represent H or Cs-6alkyl; n represents an integer of from 0-5; p is 0, 1 or 2; Ra represents CH 2
CH
2
CO
2
R
4 , CH 2
CH(OH)CO
2
R
4 or 5-tetrazolyl; and Rb is H or is selected from the group consisting of: halo, CN, NO 2 , OH, C 1
.
3 alkyl, OCI. 35 3 alkyl, haloC 1
.
3 alkyl and haloC 1
.
3 alkoxy. Another aspect of the invention that is of interest relates to a compound represented by formula I or a pharmaceutically acceptable salt or solvate thereof wherein Ring A represents an Aryl group selected from phenyl, naphthyl and tetrahydronaphthyl, a HAR group which is a 6-10 membered -5- WO 2007/111864 PCT/US2007/006806 aromatic heteroaryl or partially aromatic hetercyclyl containing 1-2 heteroatoms, 0-1 of which is O and 0 2 of which are N atoms. Within this subset of the invention, all other variables are as originally defined with respect to formula I. More particularly, another aspect of the invention that is of interest relates to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof wherein Ring A represents a member selected from the group consisting of: o co ccoc 0c 0c N 0 00 QON Within this subset of the invention, all other variables are as originally defined with respect to formula I. Even more particularly, an aspect of the invention that is of interest relates to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof wherein Ring A represents a member selected from the group consisting of: H 000 0c O00oO~ Within this subset of the invention, all other variables are as originally defined with respect to formula I. Another aspect of the invention that is of interest relates to a compound represented by formula I or a pharmaceutically acceptable salt or solvate thereof wherein n represents an integer selected from 1, 2 and 3. Within this subset of the invention, all other variables are as originally defined with respect to formula I. In particular, another aspect of the invention that is of interest relates to a compound represented by formula I or a pharmaceutically acceptable salt or solvate thereof wherein n represents an ) integer selected from 1 and 2. Within this subset of the invention, all other variables are as originally defined with respect to formula I. More particularly, another aspect of the invention that is of interest relates to a compound represented by formula I or a pharmaceutically acceptable salt or solvate thereof wherein n represents 2. Within this subset of the invention, all other variables are as originally defined with respect to formula I. 5 Another aspect of the invention that is of interest relates to a compound represented by formula I or a pharmaceutically acceptable salt or solvate thereof wherein the R' and R 2 groups represent hydrogen or 1-2 of the R' and R 2 groups are independently selected from the group consisting of: halo; OH; CI.6alkyl optionally substituted with 1-3 halo groups; CN; NR 6
R
7 ; SOpR; C 2 -4alkenyl, and a 6-10 membered Aryl group, or the R groups are taken in combination and represent a -CH 2 - or -CH 2
CH
2 -6- WO 2007/111864 PCT/US2007/006806 group, or a fused phenyl ring, unsubstituted or substituted with 1-3 groups, up to 3 of which are halo groups, and up to 2 of which are CI.
3 alkyl, haloC 1
.
3 alkyl, Cs.
3 alkoxy or haloC- 1
.
3 alkoxy groups. Within this subset of the invention, all other variables are as originally defined with respect to formula I. In particular, another aspect of the invention that is of interest relates to a compound represented by formula I or a pharmaceutically acceptable salt or solvate thereof wherein the R' groups represent hydrogen; halo; C 1 .4alkyl optionally substituted with 1-3 halo groups; CN or NR 6
R
7 ; and the R2 groups represent H, or are taken in combination and represent a -CH 2 - or a fused phenyl ring, unsubstituted or substituted with 1-3 groups, up to 3 of which are halo groups, and up to 2 of which are Cs_ 3 alkyl, haloCI.
3 alkyl, C.
3 alkoxy or haloCI.
3 alkoxy groups. Within this subset of the invention, all other variables are as originally defined with respect to formula I. Even more particularly, another aspect of the invention that is of interest relates to a compound represented by formula I or a pharmaceutically acceptable salt or solvate thereof wherein the Ri groups represent hydrogen; halo; CH 3 or CF3, and the R2 groups represent H, or are taken in combination and represent a -CH 2 - or a fused phenyl ring. Within this subset of the invention, all other S variables are as originally defined with respect to formula I. Another aspect of the invention that is of interest relates to compounds of formula I or a pharmaceutically acceptable salt or solvate thereof wherein R is selected from
N
N CO2H and I/ HN-N Within this subset of the invention, all other variables are as originally defined with respect to formula I ) More particularly, an aspect of the invention that is of interest relates toa compound of formula I or a pharmaceutically acceptable salt or solvate thereof wherein R a represents CO2H Within this subset of the invention, all other variables are as originally defined with respect to formula I Another aspect of the invention that is of interest relates to a compound of formula I or a 5 pharmaceutically acceptable salt or solvate thereof wherein Rb represents H. Within this subset of the invention, all other variables are as originally defined with respect to formula I Another aspect of the invention that is of interest relates to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof wherein each R is selected as follows: 1) 0-1 R 3 group is selected from the group consisting of: Aryl, IAR, 0 -CH 2 -Aryl, -CH 2 -HAR, -O-Aryl, -O-HAR, -O-CH 2 -Aryl and -O-CH 2 -HAR; said Aryl and HAR groups and portions of the groups above being optionally substituted with 1-2 halo atoms, and 1-2 members selected from: CN, C_6alkyl, OCi6alkyl, haloC. 3 alkyl, OCI.
3 haloalkyl, NO 2 , SOpR 5 , C 2 6alkenyl, NH2, NMez and HAR; 2) 0-3 R 3 groups are selected from: CN, oxo, NO 2 , S(O)pC,-salkyl,
NH
2 , 5 NMe 2 , C 1
.
7 alkyl, haloC.
3 alkyl, OCI.
7 alkyl, OC.
3 haloalkyl and C 2 6alkenyl, and -7- WO 2007/111864 PCT/US2007/006806 3) the remaining R 3 groups are H or halo atoms. Within this subset of the invention, all other variables are as originally defined with respect to formula I. More particularly, an aspect of the invention that is of interest relates to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof wherein each R is selected as follows: 1) 0-1 R group is selected from the group consisting of: Aryl, HAR,
-CH
2 -Aryl, -CH 2 -HA, -O-Aryl, -O-HAR, -O-CH 2 -Aryl and -O-CH 2 -HAR; said Aryl and HAR groups and portions of the groups above being optionally substituted with 1-2 halo atoms and 1-2 members selected from: CN, C 1 4alkyl, OC2_6alkyl, S(O)pCi.
6 alkyl, halomethyl, halomethoxy,
NO
2 , NMe 2 and pyrazolyl; 2) 0-1 R 3 group is selected from: CN, oxo, NO 2 , SO 2
CH
3 , NMe 2 , CI.
7 alkyl, haloCz.
3 alkyl, OCI- 7 alkyl, OCI-.
3 haloalkyl and C 2 .6alkenyl,and 3) the remaining R 3 groups are H or halo atoms. Within this subset of the invention, all other variables are as originally defined with respect to formula I Even more particularly, an aspect of the invention that is of interest relates to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof wherein each R 3 is selected as follows: each R group is selected as follows: 1) 0-1 R 3 groups represents: Aryl, wherein Aryl is selected from phenyl, naphthyl and tetrahydronaphthyl; HAR selected from pyridyl, quinolinyl, pyrimidinyl, isoxazolyl, benzoxazolyl, benzopyrazolyl, benzooxadiazolyl, indazolyl, benzofuranyl, tetrahydroquinolinyl, ) benzothiophene, benzothiazole and benzoimidazolyl;
-CH
2 -Aryl selected from benzyl; -O-Aryl selected from phenyloxy; -O-HLAR selected from pyridyloxy, benzothiazoloxy and quinolinyloxy; -0
CH
2 -Aryl selected from benzyloxy or -O-CH 2 -HAR selected from: pyridylmethoxy, furanylmethoxy, benzothiazolmethoxy and quinolinylmethoxy, said Aryl and HAR groups and portions of the groups above being optionally 5 substituted with 1-2 halo atoms and 1 member selected from: CN, Cl-4alkyl, methoxy, trifluoromethyl, trifluoromethoxy, NO 2 , and NMe 2 ; 2) 0-1 R' group is selected from: CI.
7 alkyl, haloCl- 3 alkyl, OC.- 7 alkyl and
OCI.
3 haloalkyl, and 3) the remaining R? groups are H or halo atoms. Within this subset of the 0 invention, all other variables are as originally defined with respect to formula I. Another aspect of the invention that is of interest relates to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof wherein: 5 Ring A represents an Aryl group selected from phenyl, naphthyl and tetrahydronaphthyl, a HAR group which is a 6-10 membered aromatic heteroaryl or partially aromatic hetercyclyl containing 1-2 heteroatoms, 0-1 of which is O and 0-2 of which are N atoms; -8- WO 2007/111864 PCT/US2007/006806 n represents an integer selected from 1, 2 and 3; the R' and R 2 groups represent hydrogen or 1-2 of the R' and R 2 groups are independently selected from the group consisting of: halo; OH; C 1 6alkyl optionally substituted with 1-3 halo groups; CN; NR 6 R; SOpRs; C 24 alkenyl, and a 6-10 membered Aryl group, or the R 2 groups are taken in combination and represent a -CH 2 - or -CH 2
CH
2 - group, or a fused phenyl ring, unsubstituted or substituted with 1-3 groups, up to 3 of which are halo groups, and up to 2 of which are C 1
.
3 alkyl, haloC 1
.
3 alkyl, CI.
3 alkoxy or haloC 1
.
3 alkoxy groups; Ra is selected from N
CO
2 H and /N HN-N. Rb represents H, and ; each R 3 is selected as follows: 1) 0-1 R' group is selected from the group consisting of: Aryl, HAR,
-CH
2 -Aryl, -CH2 -HAR, -O-Aryl, -O-HAR, -O-CH 2 -Aryl and -O-CH 2 -HAR; said Aryl and HAR groups and portions of the groups above being optionally substituted with 1-2 halo atoms, and 1-2 members selected from: CN, CI.ealkyl, OC.6alkyl, haloCI. ) 3 alkyl, OC 1 i.
3 haloalkyl, NO 2 , SOpR s , C 2 -6alkenyl, NH 2 , NMe 2 and HAR; 2) 0-3 R groups are selected from: CN, oxo, NO 2 , S(O)pC 1 -salkyl, NH 2 , NMe 2 , C 17 alkyl, haloC 1
.
3 alkyl, OCI.
7 alkyl, OCI.
3 haloalkyl and C 2
-
6 alkenyl, and 3) the remaining R 3 groups are H or halo atoms. Within this subset of the invention, all other variables are as originally defined with respect to formula I. 5 Examples of compounds that fall within the invention described herein are in the tables described herein. Pharmaceutically acceptable salts and solvates of the compounds disclosed in the tables are included as well. Another aspect of the invention that is of interest relates to a pharmaceutical composition comprising a compound as described above with respect to formula I in combination with a 0 pharmaceutically acceptable carrier. Another aspect of the invention that is of interest relates to a method of treating type 2 diabetes mellitus in a mammalian patient in need of such treatment comprising administering to said patient a compound as described above with respect to formula I in an amount that is effective to treat type 2 diabetes mellitus. 5 Another aspect of the invention that is of interest relates to a method of delaying the onset of type 2 diabetes mellitus in a mammalian patient in need thereof, comprising administering to the -9- WO 2007/111864 PCT/US2007/006806 patient a compound as described above in accordance with formula I in an amount that is effective to delay the onset of type 2 diabetes mellitus. Another aspect of the invention that is of interest relates to a method of treating hyperglycemia, diabetes or insulin resistance in a mammalian patient in need of such treatment which comprises administering to said patient a compound as described above in accordance with formula I in an amount that is effective to treat hyperglycemia, diabetes or insulin resistance. Another aspect of the invention that is of interest relates to a method of treating non insulin dependent diabetes mellitus in a mammalian patient in need of such treatment comprising administering to the patient an anti-diabetic effective amount of a compound in accordance with formula I as described above. Another aspect of the invention that is of interest relates to a method of treating obesity in a mammalian patient in need of such treatment comprising administering to said patient a compound in accordance with formula I as described above in an amount that is effective to treat obesity. Another aspect of the invention that is of interest relates to a method of treating 5 Syndrome X in a mammalian patient in need of such treatment, comprising administering to said patient a compound in accordance with formula I as described above in an amount that is effective to treat Syndrome X. Another aspect of the invention that is of interest relates to a method of treating a lipid disorder selected from the group consisting of dyslipidemia, hyperlipidemia, hypertriglyceridemia, ) hypercholesterolemia, low HDL and high LDL in a mammalian patient in need of such treatment, comprising administering to said patient a compound as described above with respect to formula I in an amount that is effective to treat said lipid disorder. Another aspect of the invention that is of interest relates to a method of treating atherosclerosis in a mammalian patient in need of such treatment, comprising administering to said 5 patient a compound in accordance with formula I as described above in an amount effective to treat atherosclerosis. Another aspect of the invention that is of interest relates to a method of treating a condition selected from the group consisting of: (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, 0 (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16) neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19) neuropathy, (20) Syndrome X, and other conditions and disorders where insulin resistance is a component, in a mammalian patient in need of such treatment, comprising administering to the patient a compound in accordance with formula I as described above in 5 an amount that is effective to treat said condition. Another aspect of the invention that is of interest relates to a method of delaying the onset of a condition selected from the group consisting of (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) - 10- WO 2007/111864 PCT/US2007/006806 hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16) neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19) neuropathy, (20) Syndrome X, and other conditions and disorders where insulin resistance is a component in a mammalian patient in need of such treatment, comprising administering to the patient a compound in accordance with formula I as described above in an amount that is effective to delay the onset of said condition. Another aspect of the invention that is of interest relates to a method of reducing the risk of developing a condition selected from the group consisting of (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16) neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19) neuropathy, (20) Syndrome X, and other conditions and disorders where insulin resistance is a component in a mammalian patient in need of such treatment, comprising administering to the patient a compound of formula I as described above in an amount that is effective to reduce the risk of developing said condition. Another aspect of the invention that is of interest relates to a method of treating a condition selected from the group consisting of: (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) S low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (1.3) vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16) neurodegenerative disease, (17)retinopathy, (18) nephropathy, (19) neuropathy, (20) Syndrome X, and other conditions and disorders where insulin resistance is a component, in a mammalian patient in need of such treatment, comprising administering to the patient effective amounts of a compound of formula I as 5 described above, and a compound selected from the group consisting of: (a) DPP-IV inhibitors, such as the compounds disclosed in US Pat No. 6,699,871B1 granted on March 2, 2004, incorporated herein by reference; (b) insulin sensitizers selected from the group consisting of (i) PPAR agonists and (ii) biguanides; (c) insulin and insulin mimetics; (d) sulfonylureas and other insulin secretagogues; (e) alpha glucosidase inhibitors; (f) other glucagon 0 receptor antagonists; (g) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists; (h) GIP,GIP mimetics, and GIP receptor agonists; (i) PACAP, PACAP mimetics, and PACAP receptor 3 agonists; (j) cholesterol lowering agents selected from the group consisting of (i) HMG-CoA reductase inhibitors, (ii) sequestrants, (iii) nicotinyl alcohol, nicotinic acid and salts thereof, (iv) PPAR alpha agonists, (v) PPAR alpha/gamma dual agonists, (vi) inhibitors of cholesterol absorption, (vii) acyl CoA:cholesterol 5 acyltransferase inhibitors, (viii) anti-oxidants and (ix) LXR modulators; (k) PPAR delta agonists; (1) antiobesity compounds; (m) an ileal bile acid transporter inhibitor; (n) anti-inflammatory agents excluding glucocorticoids; (o) protein tyrosine phosphatase-lB (PTP-IB) inhibitors, and (p) CB1 -11- WO 2007/111864 PCT/US2007/006806 antagonists/inverse agonists, such as rimonabant and those disclosed in W003/077847A2, published on September 25, 2003, and W005/000809 published on January 6, 2005, incorporated herein by reference, said compounds being administered to the patient in amounts that are effective to treat said condition. Another aspect of the invention that is of interest relates to a method of treating a condition selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia and dyslipidemia, in a mammalian patient in need of such treatment, comprising administering to the patient therapeutically effective amounts of a compound of formula I as described above and an HMG-CoA reductase inhibitor. More particularly, another aspect of the invention that is of interest relates to a method of treating a condition selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia and dyslipidemia, in a mammalian patient in need of such treatment, comprising administering to the patient therapeutically effective amounts of a compound of formula I as described above and an HMG-CoA reductase inhibitor wherein the I-IMG-CoA 5 reductase inhibitor is a statin. Even more particularly, another aspect of the invention that is of interest relates to a method of treating a condition selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia and dyslipidemia, in a mammalian patient in need of such treatment, comprising administering to the patient D therapeutically effective amounts of a compound of formula I as described above and an HMG-CoA reductase inhibitor, wherein the HMG CoA reductase inhibitor is a statin selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, ZD-4522 and rivastatin. Another aspect of the invention that is of interest relates to a method of reducing the risk 5 of developing a condition selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia and dyslipidemia, and the sequelae of such conditions comprising administering to a mammalian patient in need of such treatment therapeutically effective amounts of a compound of formula I as described above and an IHMG-CoA reductase inhibitor. 0 Another aspect of the invention that is of interest relates to a method for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment comprising administering to said patient effective amounts of a compound of formula I as described above and an HMG-CoA reductase inhibitor. More particularly, another aspect of the invention that is of interest relates to a method 5 for delaying the onset of, or reducing the risk of developing atherosclerosis in a human patient in need of such treatment comprising administering to said patient effective amounts of a compound of formula I as described above and an IHMG-CoA reductase inhibitor wherein the IHIMG-CoA reductase inhibitor is a statin. -12- WO 2007/111864 PCT/US2007/006806 Even more particularly, another aspect of the invention that is of interest relates to a method for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment comprising administering to said patient effective amounts of a compound of formula I as described above and an HMG-CoA reductase inhibitor wherein the HMG-CoA reductase inhibitor is a statin selected from the group consisting of: lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, ZD-4522 and rivastatin. Yet even more particularly, another aspect of the invention that is of interest relates to a method for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment comprising administering to said patient effective amounts of a compound of formula 1 as described above and an HMG-CoA reductase inhibitor wherein the HMG-CoA reductase inhibitor is simvastatin. Another aspect of the invention that is of interest relates to a method for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment comprising administering to said patient effective amounts of a compound of formula I as described above and a cholesterol absorption inhibitor. More particularly, another aspect of the invention that is of interest relates to a method for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment comprising administering to said patient effective amounts of a compound of formula I as described above and a cholesterol absorption inhibitor wherein the cholesterol absorption inhibitor is ezetimibe. ) Another aspect of the invention that is of interest relates to a method for delaying the onset or reducing the risk of developing the other diseases and conditions mentioned above, in a mammalian patient in need of such treatment comprising administering to said patient effective amounts of a compound of formula I as described above, and a cholesterol absorption inhibitor. More particularly, another aspect of the invention that is of interest relates to a method for delaying the onset or reducing the risk of developing the other diseases and conditions mentioned above, in a human patient in need of such treatment comprising administering to said patient effective amounts of a compound of formula I as described above, and a cholesterol absorption inhibitor, wherein the cholesterol absorption inhibitor is ezetimibe. Another aspect of the invention that is of interest relates to a pharmaceutical composition 3 comprising (1) a compound of formula I as described above; (2) a compound selected from the group consisting of: (a) DPP-IV inhibitors, such as those disclosed in US Pat No. 6,699,871B1 granted on March 2, 2004; (b) insulin sensitizers selected from the group consisting of(i) PPAR agonists and (ii) biguanides; (c) insulin and insulin mimetics; (d) sulfonylureas and other insulin secretagogues; (e) alpha glucosidase inhibitors; (f) other glucagon receptor antagonists; (g) GLP-1, GLP-1 mimetics and GLP-1 5 receptor agonists; (h) GIP, GIP mimetics and GIP receptor agonists; (i) PACAP, PACAP mimetics, and PACAP receptor 3 agonists; (j) cholesterol lowering agents selected from the group consisting of(i) HIMG-CoA reductase inhibitors, (ii) sequestrants, (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPAR alpha agonists, (v) PPAR alpha/gamma dual agonists, (vi) inhibitors of cholesterol absorption, -13- WO 2007/111864 PCT/US2007/006806 (vii) acyl CoA:cholesterol acyltransferase inhibitors, (viii) anti-oxidants and (ix) LXR modulators; (k) PPAR delta agonists; (1) antiobesity compounds; (m) an ileal bile acid transporter inhibitor; (n) anti inflammatory agents other than glucocorticoids; (o) protein tyrosine phosphatase-IB (PTP-1 B) inhibitors; and (p) CB1 antagonist/inverse agonists, such as rimonabant, and those disclosed in W003/077847A2 published on September 25, 2003 and WO05/000809 published on January 6, 2005, and (3) a pharmaceutically acceptable carrier. One pharmaceutical composition that is of interest is comprised of a compound of formula I as described herein, or a pharmaceutically acceptable salt or solvate thereof, in combination with a DPP-IV inhibitor selected from the group consisting of: F F F \ NH 2 0
NH
2 0 ~N N I 0N N I N F N N F
CF
3
CF
3 F F Br \ NH 2 0 Br I NH 2 0 N NN
NC
N F N F N CF CC~z
CF
3 or a pharmaceutically acceptable salt or solvate thereof in combination with a pharmaceutically acceptable carrier. Another pharmaceutical composition that is of particular interest is comprised of a 5 compound of formula I as described herein, or a pharmaceutically acceptable salt. or solvate thereof, in combination with a CB I receptor antagonist/inverse agonist, in combination with a pharmaceutically acceptable carrier. Examples of CB 1 antagonist/inverse agonists that are of particular interest in the invention described herein include rimonabant, the following which are disclosed in W003/077847A2 published on September 25, 2003: 0 (1) N-[3-(4-chlorophenyl)- 1 -methyl-2-phenylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide; (2) N-[3-(4-chlorophenyl)- 1 -methyl-2-phenylpropyl]-2- (2 -pyridylo xy)
-
2methylpropanamide ; (3) N-[3-(4-chlorophenyl)- 1-methyl-2-(3-pyridyl)propyl]-2-(4-chlorophenyloxy)-2 methylpropanamide; 5 (4) N-[3-(4-chlorophenyl)-1 -methyl-2-phenylpropyl]-2-(3,5-difluorophenyloxy)-2 methylpropanamide; -14- WO 2007/111864 PCT/US2007/006806 (5) N-[3-(4-chlorophenyl)-2-phenyl-1 -methylpropyl]-2-(3,5-dichlorophenyloxy)-2 methylpropanamide; (6) N-[3-(4-chlorophenyl)- -methyl-2-phenylpropyl]-2-(3-chlorophenyloxy)-2-methylpropanamide; (7) N-[3-(4-chlorophenyl)-2-(3,5-difluorophenyl)-1l-methylpropyl]-2-(2-pyridyloxy)- 2 methylpropanamide; (8) N-[3-(4-chlorophenyl)-1-methyl-2-phenyl-propyl]-2-(5-chloro-2-pyridyloxy)-2 methylpropanamide; (9) N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(6-methyl-pyridyloxy)-2-methylpropanamide; (10) N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(phenyloxy)-2-methylpropanamide; (11) N-[(3-(4-chlorophenyl)-1 -methyl-2-phenylpropyl]-2-(5-trifluoromethylpyridyloxy)-2 methylpropanamide; (12) N-[3-(4-chlorophenyl)-2-(3-pyridyl)- 1 -methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2 methylpropanamide; (13) N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1 -methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)- 2 methylpropanamide; (14) N-[3-(4-chlorophenyl)-2-(5-chloro-3-pyridyl)- 1 -methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy) ) 2-methylpropanamide; (15) N-[3-(4-chlorophenyl)-2-(5-methyl- 3 -pyridyl)- 1-methylpropyl]-2-(5-trifluoromethyl- 2 pyridyloxy)-2-methylpropanamide; (16) N-[3-(4-chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]- 2 -(5-trifluoromethy-2-pyridyloxy) 2-methylpropanamide; 5 (17) N-[3-(4-chlorophenyl)-2-(3-methylpheny!)-1 -methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)- 2 methylpropanamide; (18) N-[3-(4-chlorophenyl)-2-phenyl-1 -methylpropyl]-2-(4-trifluoromethyl- 2 -pyridyloxy)-2 methylpropanamide; (19) N-[3-(4-chlorophenyl)-2-phenyI-1-methylpropyl]-2-(4-trifluoromethyl-2-pyrimidyloxy)-2 0 methylpropanamide; (20) N-[3-(4-chlorophenyl)-1-methyl-2-(thiophen-3-yl)propyl]-2-(5-chloro-2-pyridyloxy)-2 methylpropanamide; (21) N-[3-(5-chloro-2-pyridyl)-2-phenyl-1 -methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2 methylpropanamide; 5 (22) N-[3-(4-methyl-phenyl)-1 -methyl-2-phenylpropyl]-2-(4-trifluorometyl-phenyloxy)-2 methylpropanamide; (23) N-[3-(4-fluoro-phenyl)-2-(3-cyano-phenyl)- -methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2 methylpropanamide; - 15 - WO 2007/111864 PCT/US2007/006806 (24) N-[3--(4-chlorophenyl)-2-(1 -indolyl)-l1 methy1)propy13-2-(5-trifluorometby-2oxypyridine- 2 -yI)- 2 methyipropanamide; (25) N-[3 -(4-chorophenyl)-2-(7-azaindol-N-yl)-l -methyl)propyl]-2-(5-trifluoromethyl2-pyridyloxy) 2-methylpropanamide; (26) N-[3-(4-chloro-phenyl)-2-( 1-indolinyl)-1 -methylpropyl]-2-(5-trifluoromlethy-2-pyridyloxy)- 2 methyipropanamide; (27) 2V[-4choope1l -N-ehlanln)lmethylpropyl]-2-(5-rifluoromethyk.2-pyridyloxy)> 2-methyipropanalnide; (28) N-3(-ehx-hnl--3caopey)lmthlrpl--5tilooebl2prdlx) 2-methylpropanamide; (29) N-[3-(4-chloropheny1)-2-(3-cyanopbeflyl)-l -methylpropyl1-2-(6-trifluoromethyl4-pyrimidyloxy) 2-methyipropanamide; (30) N-[2-(3 -cyanophenyl)- 1 ,4-dimethylpentyl]-2-(5-trifluorometby-2-pyridyloxy)- 2 methyipropanamide; (31) N-[3 -(4-chlorophenyl)-2-( 1-oxido-5-cyano-3 -pyridyl]- 1 -methylpropyl]-2-(S-trifluoromethyl- 2 pyridyloxy)-2-methylpropaflamide; (32) N-[2-(3-cyanophenyl)-3-cyclobutyl-l -methylpropy]-2-(5-trifluoromethylk2-pyridyloxy)- 2 methyipropanamnide; (33) N-[2-(3-cyanophenyl)-l-ehlhpy 2-5tilooeh -- yiyoy--mtypoaaie (34) N-[2-(3-cyanopheflyl)-3 -cyclopentyl-l -methylpropyl]-2-(5-trifluoromethyl.2-pyridyloxy)- 2 methyipropanamnide; (35) N-[2-(3-cyanopheny)-3-cycohexyl-l -methylpropyl]-2-(5-trifluoromethyl2-pyridYoxy)- 2 methylpropanamide; and in W005/000809 published on January 6, 2005, which includes the following: 3-{l l[Bis( 4 -chloropheny)methyl]azetidin3yidele}-3(3,5difluorophenyl)-2,2dimethylpropanenitrile 1-({1 -[1 -(4-chlorophenyl)pentyllazetidil-3-yl} -1 -(3 ,5-difluoropbenyl)-2-mfethyIPropafl- 2 -ol 3-((S)-(4-chlorophenyl) {3-[(1 S)-I 1 ,-iloohnl)2hdoy2mtylrplaeii- yl} methyl)benzonitrile ) 3-((S)-(4-chlorophenyl){3-[(1 S)l(,-iloohnl--lur--ehlrpIaeii- yl} methyl)benzonitrile 3-((4-chlorophenyl) 13[-35dfurpey)22dmtypoy~ztdn 1 -yl~methyl)benzonitrile 3 -((1 S)-1 - { 1 -[(S)-(3-cyanopheny1)(4-cyaflophenyl)methyl]azetidin- 3 -yl -2-fluoro-2-methylpropyl)-5 fluorobenzonitrile 5 3-[(S)-(4-chlorophenyl)(3- {( 1S)-2-fluoro-l1-[3-fluoro-5--(4H- 1,2,4-triazol-4-yI)pheflyl]- 2 methylpropyl }azetidin-l -y)methyl]benzonrtile and S-((4-chlorophenyl) {3-[( IS)-l1 (3,5-difluoropheny1)-2-fluoro-2-methylPropyl] azetidin- 1 yl} methyl)thiophene-3-carboflitrile, - 16 - WO 2007/111864 PCT/US2007/006806 as well as the pharmaceutically acceptable salts and solvates thereof, in combination with a pharmaceutically acceptable carrier. Optical Isomers - Diastereomers - Geometric Isomers - Tautomers Many of the compounds of formula I contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention includes all such isomeric forms of the compounds, in pure form as well as in mixtures. Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers. Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form known as keto enol tautomers. The individual tautomers as well as mixtures thereof are encompassed with the compounds of Formula I. Salts and Solvates Salts and solvates of compounds of formula I are included in the present invention. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable ) substantially non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids, as well as salts that can be converted into pharmaceutically acceptable salts. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable 5 organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, 0 piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, 5 hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids. -17- WO 2007/111864 PCT/US2007/006806 Solvates as used herein refers to the compound of formula I or a salt thereof, in association with a solvent, such as water. Representative examples include hydrates, hemihydrates, trihydrates and the like. References to the compounds of Formula I are intended to include the pharmaceutically acceptable salts and solvates. This invention relates to a method of inhibiting the activity of glucagon by antagonizing the glucagon receptor, thereby reducing the rate of gluconeogenesis and glycogenolysis, and the concentration of glucose in plasma. The compounds of formula I can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of disease states in mammals associated with elevated levels of glucose, comprised of combining the compound of formula I with the carrier materials to provide the medicament. Dose Ranges The prophylactic or therapeutic dose of a compound of formula I will, of course, vary with the nature or severity of the condition to be treated, the particular compound selected and its route of administration. It will also vary according to the age, weight and response of the individual patient. In general, the daily dose range lies within the range of from about 0.001 mg to about 100 mg per kg body weight, preferably about 0.01 mg to about 50 mg per kg, and more preferably 0.1 to 10 mg per kg, in ) single or divided doses. It may be necessary to use dosages outside of these limits in some cases. The terms "effective amount", "anti-diabetic effective amount" and the other terms appearing throughout the application addressing the amount of the compound to be used refer to the dosage ranges provided, taking into account any necessary variation outside of these ranges, as determined by the skilled physician. Representative dosages of compounds of formula I, as well as the pharmaceutically 5 acceptable salts and solvates thereof, for adults range from about 0.1 mg to about 1.0 g per day, preferably about I mg to about 500 mg, in single or divided doses. Representative dosages of compounds used in combination with the compounds of formula I are known, or the determination thereof is within the level of skill in the art, taking into account the description provided herein. When intravenous or oral administration is employed, a representative dosage range is D from about 0.001 mg to about 100 mg (preferably from 0.01 mg to about 10 mg) of a compound of Formula I per kg of body weight per day, and more preferably, about 0.1 mg to about 10 mg of a compound of formula I per kg of body weight per day. When used in combination with other agents, the dosages noted above for the glucagon antagonist are provided along with the usual dose for the other medication. For example, when a DPP-IV 5 inhibitor such as those disclosed in US Pat No. 6,699,871B1, is included, the DPP-IV inhibitor can be used in an amount ranging from about 1.0mg to as high as about 1000mg, preferably about 2.5mg to about 250mg, and in particular, about 50 mng or about 100 mg administered in single daily doses or in divided doses as appropriate. Similarly, when the glucagon receptor antagonist is used in combination - 18- WO 2007/111864 PCT/US2007/006806 with a CB 1 antagonist/inverse agonist, the CB1 antagonist/inverse agonist can be used in an amount ranging from as low as about 0.1 mg to as high as about 1000 mg, more particularly, in an amout ranging from about 1.0 mg to about 100 mg, and even more particularly, in an amount from about 1.0 mg to about 10 mg, administered in single daily doses or in divided doses as appropriate. Examples of doses of CB1 antagonist/inverse agonist include 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg and 10mg. Pharmaceutical Compositions As mentioned above, the pharmaceutical composition comprises a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier. The term "composition" encompasses a product comprising the active and inert ingredient(s), (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from the combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions between ingredients. Preferably the composition is comprised of a compound of formula I in an amount that is effective to treat, prevent or delay the onset of type 2 diabetes mellitus, in combination with the pharmaceutically acceptable carrier. Any suitable route of administration may be employed for providing a mammal, especially a human with an effective dosage of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Examples of dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols and the like, with oral tablets being preferred. In preparing oral compositions, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like, in the case of oral liquids, e.g., suspensions, elixirs and solutions; or carriers such as starches, 5 sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solids, e.g., powders, capsules and tablets. Solid oral preparations are preferred. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. In addition to the common dosage forms set out above, the compounds of Formula I may D also be administered by controlled release means and/or delivery devices such as those described in U. S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200 and 4,008,719. Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous 5 liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion. Such compositions may be prepared by any acceptable pharmaceutical process. All such methods include the step of combining the active ingredient(s) with the carrier components. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient(s) with a liquid or finely divided -19- WO 2007/111864 PCT/US2007/006806 solid carrier component, and then, if necessary, manipulating the blend into the desired product form. For example, a tablet may be prepared by compression or molding. Compressed tablets may be prepared by compressing free-flowing powder or granules, containing the active(s) optionally mixed with one or more excipients, e.g., binders, lubricants, diluents, surfactants and dispersants. Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid. Desirably, each tablet may contain, for example, from about 0.1 mg to about 1.0 g of the active ingredient and each cachet or capsule contains from about 0.1 mg to about 500 mg of the active ingredient. The following are examples of pharmaceutical dosage forms containing a compound of Formula I: Injectable Suspension (im.) mg/mL Tablet Mg/tablet Compound of Formula 1 10.0 Compound of Formula 1 25.0 Methylcellulose 5.0 Microcrystalline Cellulose 415 Tween 80 0.5 Povidone 14.0 Benzyl alcohol 9.0 Pregelatinized Starch 4.35 Benzalkonium chloride 1.0 Magnesium Stearate 2.5 Water for injection t.d. 1.0 mL Total 500mg Capsule mg/capsule Aerosol Per Canister Compound of Formula 1 25.0 Compound of Formula 1 250 mg Lactose 735 Lecithin, NF Lig. Conc. 1.2 mg Mg Stearate 1.5 Trichloromethane, NF 4.025g Total 600mg Dichlorodifluoromethane, NF 12.15g Combination Therapy As previously described, the compounds of Formula I may be used in combination with other drugs that are used in the treatment/prevention/delaying the onset of type 2 diabetes mellitus, as 5 well as other diseases and conditions described herein, for which compounds of Formula I are useful. Other drugs may be administered, by a route and in an amount commonly used, contemporaneously or sequentially with a compound of Formula 1. When a compound of Formula I is used contemporaneously with one or more other drugs, a combination pharmaceutical composition containing such other drugs in addition to the compound of Formula I is preferred. Accordingly, the pharmaceutical compositions of the 0 present invention include those that alternatively contain one or more other active ingredients, in addition to a compound of Formula I. Examples of other active ingredients that may be combined with a compound of Formula I, either administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) biguanides (e g., buformin, metformin, phenformin), (b) PPAR agonists (e.g., troglitazone, pioglitazone, rosiglitazone), (c) insulin, (d) somatostatin, (e) alpha-glucosidase -20 - WO 2007/111864 PCT/US2007/006806 inhibitors (e.g., voglibose, miglitol, acarbose), (f) DPP-IV inhibitors, such as those disclosed in US Pat No. 6,699,871B1 granted on March 2, 2004 (g) LXR modulators and (h) insulin secretagogues (e.g., acetohexamide, carbutamide, chlorpropamide, glibornuride, gliclazide, glimerpiride, glipizide, gliquidine, glisoxepid, glyburide, glyhexamide, glypinamide, phenbutamide, tolazamide, tolbutamide, tolcyclamide, nateglinide and repaglinide), and CB 1 inhibitors, such as rimonabant and those compounds disclosed in W003/077847A2 published on September 25, 2003 and in WO05/000809 Al published on January 6, 2005. The weight ratio of the compound of the Formula I to the second active ingredient may be varied within wide limits and depends upon the effective dose of each active ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the Formula I is combined with a PPAR agonist the weight ratio of the compound of the Formula I to the PPAR agonist will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the Formula I and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. For combination products, the compound of formula I may be combined with any other active ingredients and then added to the carrier ingredients; alternatively the order of mixing may be varied. Examples of pharmaceutical combination compositions include: (1) a compound according to formula I, (2) a compound selected from the group consisting of : (a) DPP-IV inhibitors; (b) insulin sensitizers selected from the group consisting of (i) PPAR agonists and (ii) biguanides; (c) insulin and insulin mimetics; (d) sulfonylureas and other insulin secretagogues; (e) a-glucosidase inhibitors; (f) CB1 receptor antagonists/inverse agonists; (g) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists; (h) GIP, GIP mimetics, and GIP receptor agonists; (i) PACAP, PACAP mimetics, and PACAP receptor 3 agonists; (j) cholesterol lowering agents selected from the group consisting of (i) HMG-CoA reductase inhibitors, (ii) sequestrants, (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPAR alpha agonists, (v) PPAR alpha/gamma dual agonists, (vi) inhibitors of cholesterol absorption, (vii) acyl CoA:cholesterol acyltransferase inhibitors, (viii) anti-oxidants and (ix) LXR modulators; (k) PPAR delta agonists; (1) antiobesity compounds; (min) an ileal bile acid transporter inhibitor; (n) anti-inflammatory agents other than glucocorticoids; and (o) protein tyrosine phosphatase-lB (PTP-1B) inhibitors; (p) CB 1 3 antagonistlinverse agonists and (3) a pharmaceutically acceptable carrier. The compounds of formula I can be synthesized in accordance with the general schemes provided below, where R' - R 3 , Ra, Rb, R 4 and A are defined as above. Throughout the synthesis schemes, abbreviations are used with the following meanings unless otherwise indicated: a = a ueous uLi, n-BuLi = n-butyllithium u= butyl, t-Bu= t-butyl _n and Bnzl = benzyl OC, Boc = t-butyloxycarbonyl CBZ, Cbz = Benzyloxycarbonyl -21 - WO 2007/111864 PCT/US2007/006806 DABCO = 1,4-diazabicyclo[2.2.2moctane iPrOH = isopropanol DCC = Dicyclohexylcarbodiimide DCM = dichloromethane DIEA = diisopropylethylamine DMF = NN-dimethylformamide dppf = 1,1 '-bis(diphenylphosphino) riflate = trifluoromethanesulfonate ferrocene DMSO = dimethylsulfoxide EDC = ] ethyl 3-(3-dimethylaminopropyl)-carbodiimide DIAD = diisopropylazodicarboxylate Et = ethIyl DMAP = 4-Dimethylaminopyridine EtOH = ethanol SI= electrospray ionization NMR= nuclear magnetic resonance FAB-mass spectrum= Fast atom bombardment-mass EtOAc = ethyl acetate = ivso s ectroscopy eq. = equivalents) PLC = High pressure liquid chromatography HOAc = acetic acid LAH = Lithium aluminum hydride LCMS, LC-MS= high pressure liquid t/C = platinum on activated carbon chromatography mass spectrometry HOBT, HOBt = Hydroxybenztriazole PBS = phosphate o te buffered saline LHMDS = lithium KHMmDS = potassium bis(triethylsilyl)amide bis(trimeth ylsilyl)amide Wie = methyl TFA = Trifluoroacetic acid Ph = phenyl TMS = Trimethylsilane THF = Tetrahydrofuran NMe2 = dimethylamino C6H11 = cyclohexyl 2CIPh = 2-ehlorophel iPr, iPr isopropyl Py, Pyr = pyridyl PyBOP = Benzotrazol-1-yloxytripyrrolidinophosphonium 2,4-diCIPh = 2,4-dichlorophenylhxauoposht hexafluorophosphate. TLC = thin layer chromatography _dtC = palladium on activated carbon In one embodiment of the present invention, the compounds I may be prepared from alkyl 4-[(aryl)cycloalkyl]benzoate and alkyl 4-[(heteroaryl)cycloalkyl]benzoate intermediates 5, where R! 0 represents a CI-4 alkyl group. Such compounds 5 may be prepared by a variety of procedures by those skilled in the art. (R')2 (R )4 Rb (R2)2 R
CO
2 R - 22 - WO 2007/111864 PCT/US2007/006806 5 One such procedure when AR 3 is a 4-hydroxyphenyl group is shown in Scheme 1. Reaction of a cyclic ketone I with phenol in presence of an acid such as concentrated HCI (aq) orp toluenesulfonic acid provides the diphenol 2 (J. March, Advanced Organic Chemistry, 4 ed.; Wiley: New York, 1992; p. 548). Monoprotection of one of the phenolic groups, for example as a benzyl ether as shown in Scheme 1, may be achieved by reaction of the diphenol with an equivalent of benzyl bromide in a solvent such as DMF and a base such as K 2 CO3 or CsCO 3 for 1 to 16 h at ambient or elevated temperatures. The monoprotected product 3a may be separated as necessary from unreacted starting material 2 and the bis-benzylated product. The remaining phenolic group may then be converted to the trifluoromethanesulfonate 4a by reaction with trifluoromethanesulfonic anhydride in an aprotic solvent such as DCM in presence of a base such as pyridine at reduced temperatures for 0.5 to 16 h. Reaction of the trifluoromethanesulfonate under a CO atmosphere in presence of a metal catalyst such as Pd(OAc) 2 , a ligand such as 1,1 '-bis(diphenylphosphino)ferrocene and a base such as DIEA in an alcohol solvent such as MeOH or BuOH at elevated temperatures for 1 to 24 h provides the corresponding alcohol ester 5a. If so desired, the benzyl group may be removed, for example by hydrogenation using catalytic palladium on carbon under a hydrogen atmosphere for 1 to 24 h, to provide the phenol ester 5b. Scheme 1 OH OBn (R\)2 (R')2 BnB (R') 2 . Tf 2 0 _0
(R
2
)
2 (R)2 Cs2CO, DMF (R conc. HCI, 400 C
(R
2
)
2 Py, CM S2 OH 3a OH OBn OBn OH (RCo)2 CO (RH) 2 2 (R1)2 (R2)" Pd(OAc) 2 , dppf (R) 2 MeO (R 2
)
2 " 2 DCM, MeOH, 600 C OTf 5a C02Me 5b C0 2 Me 4a D In an alternative approach, the phenol ester 5b may be obtained from the bis-phenol 2 as depicted in Scheme 2. Thus, conversion of 2 to the monotrifluoromethanesulfonate 6 by reaction with an equivalent of trifluoromethanesulfonic anhydride in an aprotic solvent such as DCM in presence of a base such as pyridine at reduced temperatures for 0.5 to 16 h, followed by carbonylation of the trifluoromethanesulfonate as described in Scheme 1, provides the phenolic ester 5b. 5 -23 - WO 2007/111864 PCT/US2007/006806 Scheme 2 OH Tf 2 O R co 2 .5b Py, DCM R n / \ Pd(OAc) 2 , dppf DIEA, MeOH, 600 C 6 OTf Benzoate esters 5 may also be prepared as shown in Scheme 3. Addition of an alkyllithium solution such as n-butyllithium in hexanes to an aryl or heteroaryl halide (R 3
)
4 A-X (X = Br, I) in an aprotic solvent such as THF at reduced temperatures, followed by reaction of the resultant aryllithium or heteroaryllithium species (R 3
)
4 A-Li with cyclic ketone 1, provides the corresponding alcohol 7. Reaction of the alcohol with a phenol in presence of an acid such as p-toluenesulfonic acid for 0.5 to 16 h, usually at elevated temperatures, provides the phenol intermediate 3. In some cases, extremely strong acids such as trifuoromethanesulfonic acid must be employed for the alkylation to occur (D. Klumpp et al, J Org. Chem. 1999, 64, 6702). As described in Scheme 1 (vide supra), conversion of the phenol to the trifluoromethanesulfonate 4, followed by carbonylation in an alcohol solvent R!OH, provides the corresponding ester intermediate 5. Scheme 3 (R)41) n-BuU Tf2O ( R )2 A ,y CO( RbK DIEA, RIOH, heat (2 OH H (R2) Py, DCM (k2) ,><R Pd(OAC) 2 , dppl' DIEA, R'OH, heat 4 OTf Ester intermediates 5 may readily be converted to final products I using methods known to those skilled in the art. Shown in Scheme 4, saponification of the ester 5 may be achieved using a base such as aqueous lithium- or sodium hydroxide in a polar solvent such as tetrahydrofuran, dioxane, 0 methanol, ethanol or a mixture of similar solvents to provide carboxylic acid 8. The acid may then be elaborated with the appropriate amine H 2 NRa using a coupling reagent such as 1-ethyl-3-(3 dimethylaminopropyl)-carbodiimide (EDC) and 1-hydroxybenzotriazole (HOBt), or benzotriazole-1 yloxytrispyrrolidino-phosphonium hexafluorophosphate (PyBOP) and a base, generally -24- WO 2007/111864 PCT/US2007/006806 diisopropylethylamine, in a solvent such as N,N-dimethylformamide (DMF) or methylene chloride for 0.5 to 48 h at ambient or slightly elevated temperatures. For compounds I where Ra = -CH 2
CH
2
CO
2
R
4 or
-CH
2
CH(OHI)CO
2
R
4 , and R 4 = CI-6alkyl, the ester may be readily cleaved to provide the carboxylic acid (R = H) by treatment with a base such as aqueous lithium or sodium hydroxide in a polar solvent such as tetrahydrofuran, dioxane, methanol, ethanol or a mixture of similar solvents at ambient or elevated temperatures. Additionally, when R 4 is a tert-butyl group it is conveniently removed by treatment with an acid such as trifluoroacetic acid, commonly as a 1:1 mixture with methylene chloride, for 0.5 to 8 h at ambient temperature. Scheme 4 (R)2 A (R 3
)
4 (R )2.>,.. LUOH Rb H 2 NRa 5 (R2 (R) 2 / EDC, HOBt, ' DIEA, DMF 8 C0 2 H As will be known to those skilled in the art, in all schemes, the product I and all synthetic intermediates may be purified from unwanted side products, reagents and solvents by recrystallization, trituration, preparative thin layer chromatography, flash chromatography on silica gel as described by W. 5 C. Still et al, J. Org. Chem., 1978, 43, 2923, or reverse-phase IIPLC. Compounds purified by HPLC may be isolated as the corresponding salt. Additionally, in some instances compound 2, previous or subsequent intermediates, or final compound I may be comprised of a mixture of enantiomers or diastereomers, including cis/trans diastereomers. As will be known to those skilled in the art, such enantiomers and diastereomers may be 0 separated by various methods including crystallization, chromatography using a homochiral stationary phase and, in the case of diastereomers, normal-phase and reverse-phase chromatography. In some cases, the product I, the penultimate ester 9, the benzoate ester 5 and other intermediates from the reactions described in the schemes will be further modified. These manipulations may include, but are not limited to, substitution, reduction, oxidation, alkylation, acylation, and 5 hydrolysis reactions, which are commonly known to those skilled in the art. For illustrative purposes, transformations depicted in the following schemes are shown for AR 3 = 4-hydroxyphenyl; this is in no way intended to limit the invention, however, as other hydroxylated aromatic and heteroaromatic groups, as well as other AR 3 groups such as aryl- and heteroaryl halides, may undergo transformations analogous to those described below. 0 As shown in Scheme 5, an aromatic or heteroaromatic hydroxyl group A-OH of intermediates such as 5b may be readily alkylated with an alkyl- or benzyl halides IR"X (X = Cl, Br or I) - 25 - WO 2007/111864 PCT/US2007/006806 in a solvent such as DMF and a base such as K 2
CO
3 or CsCO 3 at ambient or elevated temperatures to provide the corresponding ether 5c. Such ethers may also be readily prepared under Mitsunobu conditions, involving reaction of the aromatic hydroxyl group A-OH with the corresponding alkyl or benzyl alcohol R"OH in an aprotic solvent such as DCM or TI-IF in presence of a phosphine such as triphenylphosphine and an azodicarbonyl compound such as DIAD (0. Mitsunobu, Synthesis 1981, p. 1). The ether 5 may then be carried on to final products I as described in Scheme 4 (vide supra) by saponification of the ester to give acid 8a, then coupling of the acid to the desired amine such as, for example, 3-alanine tert-butyl ester as shown in Scheme 5 to provide compound Ib. If so desired, the ester may be removed as described above (vide supra) to provide the carboxylic acid Ic. Also depicted in Scheme 5, the order of reactions may be reversed, with ester 5b first being converted to amide La using the procedures outlined in Scheme 4 (vide supra), followed by alkylation of the phenolic group to give ether intermediate lb. Again, removal of the tert-butyl group if so desired provides carboxylic acid Ic. Scheme 5 0- RI O': Rii SUOH 5b R"X (R 1
)
2 - dioxane/H 2 0 Cs 2
CO
3 , DMF (R2)2 (R 2
)
2 UOH 5c CO 2 Me 8a C 2 H dioxane/H 2 O 1 H 2 OtBu
H
2 N Otu EDC, HOBt, EDC, HOBt, DIEA, DMF DIEA, DMF O-- Rii OR OH 2(R')2 - (R 1
)
2 (R')2N 1 RX 1:1 TFA/DCM 27(R2)2(R) (R2) 2
NCS
2
CO
3 , DMF (W)0 (R2 2-
°
-* o la lb HN lc HN HN I HN. 0 OtBu OH OtBu O 5 Shown in Scheme 6, the phenol ester 5b may be converted to the aryl trifluoromethanesulfonate 5d by reaction with trifluoromethanesulfonic anhydride in the presence of a base such as pyridine in an aprotic solvent such as DCM. The aryl trifluoromethanesulfonate may be further elaborated using procedures known to those skilled in the art. For example, reaction of Sd with - 26 - WO 2007/111864 PCT/US2007/006806 aryl-, heteroaryl-, alkyl- or alkenylboronic acids Rii-B(OH) 2 in the presence of a catalyst such as palladium acetate and ligand such as tri-o-tolylphosphine and a base such as cesium carbonate in a solvent such as toluene at elevated temperatures for 0.5 to 16 h provides the corresponding carbon-linked compounds 5e (A. Suzuki, J. Organomet. Chem. 1999, 576, 147). Aryl trifluoromethanesulfonates such as 5d may also be coupled to various heteroatomic compounds including amines, amides, alcohols, phenols, thiols and nitrogenous heterocycles to provide the corresponding heteroatom-linked species (S. Ley and A. Thomas, Angew. Chem. Int. Ed. 2003, 42, 5400). For example, also shown in Scheme 6, reaction of aryl triflate 5d with an alkyl or aryl amine HNRiVRV in presence of a catalyst such as Pd(OAc) 2 , a ligand such as 2-(di-tert-butylphosphino)biphenyl and a base such as sodium tert-butoxide in an aprotic solvent such as toluene at elevated temperatures provides the aniline compound 5f (J.. Org. Chem. 2000, 65, 1158). All intermediates 5e, 5f, 9d and 9e may be converted to final products I as described in Scheme 4 (vide supra). Amide compound Ja may also be converted to trifluoromethanesulfonate intermediate 9 by reaction with trifluoromethanesulfonic anhydride in the presence of a base such as pyridine in an aprotic solvent such as DCM at reduced temperatures. The trifluoromethanesulfonate may then be analogously modified to provide the corresponding products Id and le. Scheme 6 OH OTf R i (R)2 . (R)2- RiiiB(OH)2 (R')2
(R
1
)
2 - ~ T 2 0 RK_____ (R2 Pyridine, DCM (R )2 Pd(OAc), ligand (R2)2 (R2 / DCMK Cs 2 C0 3 , toluene ~C(0)Y C(0)Y 5b: Y = -OMe C(O)Y 5d: Y = ) e: Y -OMe C(O)Y Y-OM a: Y = -HN(CH 2
)
2
CO
2 tBU 9: Y =
-HN(CH
2
)
2
CO
2 tBu Id Y = -HN(CH 2
)
2
CO
2 tBu HNRIVRv Pd(Ac) 2 , ligand NaOtBu, toluene, 95 oC (R)NRR (kW2)2~ , C(O)Y 5f: Y = -OMe le: Y = -HN(CH 2
)
2
CO
2 tBu 0 Hydroxyaromatic groups A-OH may also be readily halogenated. For example, as depicted in Scheme 7, reaction of phenol 51 with halogenating agents such as N-halosuccinimides (halo = -27 - WO 2007/111864 PCT/US2007/006806 Cl, Br, I) can provide the mono-halogenated intermediates 5g and bis-halogenated compounds 5i-1. In addition, treatment of Sb in neat SO 2 C1 2 at 50 oC for 16 h cleanly provides the bis-chloride 5j (Org. Synth. 1955, p. 267), while reaction of 5b with one equivalent benzyltrimethylammonium dichloroiodate in a mixed solvent of MeOH/DCM in presence of a base such as CaCO 3 at ambient temperature for 1 to 16 h provides mainly the monoiodide 5i (Heterocycles, 2002, 56, 465). The phenolic group may then be alkylated as described in Scheme 5 (vide supra), or when X = Cl, the phenol may be converted to the trifluoromethanesulfonate and further modified as outlined in Scheme 6 (vide supra). Also depicted in Scheme 7, the bromophenol 5h and iodophenol 5i may be further elaborated to provide fused heterocycles by those skilled in the art. For example, reaction of iodophenol Si with a terminal alkyl or aryl alkyne HCCR'~ in a solvent such as DMIF containing a catalysts such as Cul and PdCI 2 (Ph 3
P)
2 , a base such as DIEA provides the 2-substituted benzofuran 5m (Synthesis, 1986, p. 749). Reaction of 5i with an alkyne RviiCCR"iii under a CO atmosphere in presence of Zn(CN) 2 and Pd 2 dba 3 , and a ligand such as 1,1 '-bis(diphenylphosphino)ferrocene in DMF at elevated temperatures provides the coumarin 5n (J. Organomet. Chem. 2003, p. 687). The intermediates thus derived from 5b may then be carried on to final products I as described in Scheme 4 (vide supra). Scheme 7 OH OH X OH (RI)2 NXS (R')2 X (RI)2 X (R?2< X=CI, Br, I (R2)' , (R?2 ' /N 5b CO 2 5.: X=CI CO 2 Me 5j: X=CI O2M 5h: X=Br 5k: X=Br 5i: X= I 51:X= I H Rvi RVI- -Rv"i Cul, PdCI 2 (Ph 3
P)
2 Zn(CN) 2, Pd 2 dba 3 , dppf DIEA, DMF, 650 C MF O RO 0 (R)N / \ / / \ / R"u (RI)') (RW)2 (R2)2 (R)2 5m CO 2 Me 5n CO 2 Me General Experimental: Chemical reactions were monitored by LC-MS, and the purity and identity of the 0 reaction products were assayed by LC-MS using one of the following conditions: -28- WO 2007/111864 PCT/US2007/006806 Method A: Column: Waters Xterra C18 (3.0 x 50 mm). Gradient: 10-100% CH 3 CN (containing 0.05%
TFA)/H
2 0 (containing 0.06% TFA) over 3.75 min @ 1 mL/min Method B: Column: MetaChem Polaris (4.6 x 50 mm). Gradient: 5-95% CH 3
CN/H
2 0, (both with 0.05 % TFA) over 2.5 min @ 2.5 mL/min Method C: Column: Waters Xterra C18 (3.0 x 50 mm). Gradient: 10-98% CH 3 CN (containing 0.05%
TFA)/H
2 0 (containing 0.06% TFA) over 3.25 min @ 1.5 mL/min Method D: Column: Waters Xterra C18 (3.0 x 50 mm). Gradient: 10-98% CH 3 CN (containing 0.05%
TFA)/H
2 0 (containing 0.06% TFA) over 1.25 min @ 1.5 mL/min Method E: Column: Waters Xterra C18 (3.0 x 50 mm). Gradient: 10-100% MeCN (containing 0.05% formic acid)/H 2 0 (containing 0.06% formic acid) over 3.75 min @ 1 mL/min Preparative IPLC was performed on either a YMC-Pack Pro C18 column (150 x 20 mm i.d.) or a Kromasil 100-10 C8 column (100 x 30 mm i.d.) at an initial flow rate of 4 mL/min for 1.35 min, followed by 20 mL/min for 10.6 min. The gradients employed during the faster part of the run are described, and all runs were followed with 100% organic at 20 mL/min for 0.5 min. Flash chromatography on silica gel was performed using pre-packed silica gel columns on a Biotage Horizon or Biotage SP-1 instrument equipped with a UV detector using the gradients described in the experimental section. The following examples are provided so that the invention might be more fully understood. They should not be construed as limiting the invention in any way. INTERMEDIATE I 0 - OMe 5 OH Step A: 44'-Cyclobutane- 1,1-divldiphenol Cyclobutanone (1.2 g, 17 mmol) and phenol (4.8 g, 51 mmol) were stirred in concentrated HCI (7 mL) at 40 oC for 72 h. The resulting slurry was filtered and the filter cake was dissolved in EtOAc and washed with saturated NaHCO 3 (aq) and brine. The organic layer was 0 concentrated to give a solid which was recrystallized from EtOAc/CH 2 Cl 2 to provide the title compound. LCMS (ESI, neg. ion): m/z = 239 [M- H]; 479 [2M-H]. 'H NMR (500 MHz, CD 3 OD): 8 7.10 (d,J= 8.6 Hz, 4 H), 6.70 (d, J = 8.6 Hz, 4 H), 2.65 (t, J = 7.5 Hz, 4 H), 1.93 (quint, J = 7.5 Hz, 2 H). - 29 - WO 2007/111864 PCT/US2007/006806 Step B: 4- (4_H-droxvphenvl)cyclobutVllDhenyl trifluoromethanesulfonate To title compound from the previous step (3.88 g, 16.2 mmol) suspended in DCM was added pyridine (3.9 mL, 49 mmol). The mixture was cooled in an ice-water bath and trifluoromethanesulfonic anhydride (2.7 mL, 16 mmol) was added slowly via syringe. The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched by the addition of 2 N HC1, extracted with EtOAc, and the organic phase was concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with a gradient of 25% to 66% EtOAc/hexanes to provide the title compound as colorless oil. LCMS (ESI, neg. ion): m/z = 371 [M - H]-. 1H NMR (500 MHIz,
CD
3 OD): 8 7.45 (d, J = 8.9 Hz, 2 H), 7.25 (d, J= 8.7 Hz, 2 H), 7.16 (d, J = 8.7 Hz, 2 H), 2.65 (t, J= 7.5 Hz, 4 H), 1.93 (quint, J = 7.5 Hz, 2 H). Step C: Methyl 4-[l-(4-hydroxyphenyl)yclobutvllbe nz oate To a solution of the title compound from the previous step (4.5 g, 12 mmol) in MeOH (8 mL) were added dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II), dichloromethane adduct (1.5 g, 1.8 mmol) and DIEA (8.3 mL, 48 mmol). The mixture was stirred under a CO atmosphere (balloon) at 50 'C for 16 h. The resulting mixture was passed through a fritted funnel and the filtrate was concentrated and purified by flash chromatography on silica gel eluting with a gradient of 12% to 80% EtOAc/hexanes to provide the title compound as a solid. LCMS (ESI, neg. ion): m/z = 281.0 [M - H] ". 'H NMR (500 MHz, CD 3 OD): 5 7.
9 1 (d, J = 8,5 Hz, 2 H), 7.39 (d, J= 8.5 Hz, 2 H), 7.15 (d, J= 8.5 Hz, 2 ) H), 3.86 (s, 3 H), 2.77-2.66 (min, 4 H), 2.00-1.87 (min, 2 H). INTERMEDIATE 2 HOO MeO Methyl 4-[ 1-(4-hydroxvphenyl)yclopentylkbenzoate 5 The title intermediate was prepared using procedures similar to those used for the synthesis of Intermediate 1. LCMS (ESI, neg. ion): mn/z = 295.2 [M - H] ". -30- WO 2007/111864 PCT/US2007/006806 INTERMEDIATE 3 HO MeO Methyl 4-2-(4-hydroxyphenyl)-2,3-dihydro-l H-inden-2-vllbenzoate The title intermediate was prepared using procedures similar to those used for the synthesis of Intermediate 1. LCMS (ESI, neg. ion): m/z = 343.1 [M - H]-. INTERMEDIATE 4 HO CO 2 Me Methyl 4-[2-(4-hydroxvphenVl)-1,2,3,4-tetrahydronaphthalen-2-vyl]benzoate The title intermediate ) was prepared using procedures similar to those used for the synthesis of Intermediate 1. LCMS (ESI, neg. ion): m/z = 357.2 [M - I] . INTERMEDIATE 5, ISOMERS A and B
F
3 C OH SC 00 5 METHOD 1 Step A: 44'-[4-(Trifluoromethyl)cyclohexane-l,1-diylldiphenol A solution of 4-(trifluoromethyl)cyclohexanone (1.13 g, 6.8 mmol) and phenol (2.01 g, 21.4 mmol) in 3 mL of concentrated HCI (aq) was stirred at 40 'C for 18 h. The reaction mixture was diluted with EtOAc and saturated aqueous NaHCO 3 was slowly added. The organic layer was collected -31- WO 2007/111864 PCT/US2007/006806 and the aqueous layer was extracted twice with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0% to 40% EtOAc/hexanes over 10 column volumes, then 40% to 100% EtOAc/hexanes over 5 column volumes, affording the title compound as a white solid. LCMS (ESI, neg. ion): m/z= 335.1 [M-1] -. 'H NMR (500 MHz, CD30D) 8 7.17 (d, J = 8.7 Hz, 2H), 6.96 (d, J= 8.7 Hz, 2H), 6.76 (d, J = 8.7 Hz, 2 H), 6.60 (d, J= 9 Hz, 2H), 2.69 (d, J = 13 Hz, 2 H), 2.24 (m, 1 H), 1.91 (t, 2H), 1.84 (br d, 2H), 1.49 (q, 2H). Step B: 4-l-4-(Benzyloxy)henyl-4-(trfluoromehyl)yloh lphen To a solution of the title compound from the previous step (988 mg, 2.9 mmol) in 6mL of DMF was added Cs 2
CO
3 (945 mg, 2.9 mmol), then benzyl bromide (0.35 mL, 2.9 mmol). The reaction was allowed to stir at ambient temperature overnight, then partitioned between EtOAc and saturated aqueous NaHCO 3 . The organic layer was collected and the aqueous layer was extracted twice with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0% - 35% EtOAc/hexanes over 10 column volumes, then 35% - 100% EtOAc/hexanes over 5 column volumes to afford the title compound as a foamy white solid. LC-MS (ESI): m/z = 449.18 [M+23] . i Step C: 4-[ 1-[ 4 -(Benzvloxy)phenyll-4-(trifluoromethyl)cYclohexyllphen1 trifluoromethanesulfonate )To a solution of the title compound from the previous step (432 mg, 1 mmol) and pyridine (0.40 mL, 5 mmol) in 5 mL of DCM was added dropwise trifluoromethanesulfonic anhydride (0.34 mL, 2 mmol). The reaction was allowed to stand at ambient temperature for 16 h, then diluted with DCM and poured into 2 N HCI. The organic layer was collected and the aqueous layer was washed twice with DCM. The combined organic layers were concentrated under reduced pressure. The residue was 5 purified by flash chromatography on silica gel, eluting with a gradient of 0% - 30% EtOAc/hexanes over 10 column volumes, then 30% - 100% EtOAc/hexanes over 5 column volumes, affording the title compound as a yellow oil. LC-MS (ESI): 559.09 [M+1] . Step D: Methyl 4-l1[ 4 -(benzvloxy)phell-4-(trifluoromethyl)cyclohexylbenzoate 0 To a solution of the title compound from the previous reaction (194 mg, 0.35 mmol), palladium(II) acetate (11 mg, 0.05 mmol), and 1,1'-bis(diphenylphosphino)ferrocene (58 mg, 0.1 mmol) in 2.5 mL MeOH was added DIEA (0.24 mL, 1.4 mmol). The flask was heated under a CO atmosphere (balloon) at 50 *C for 16 h. The solvent was removed under reduced pressure and the resulting residue was purified by flash chromatography on silica gel eluting with a gradient of 0% - 15% EtOAc/hexanes 5 over 10 column volumes, affording the title compound as a foamy white solid. LC-MS (ESI): m/z = 469.19 [M+I]-. -32- WO 2007/111864 PCT/US2007/006806 Step E: Methyl 4-[1-(4-hydroxypheny)-4-(trifluoromethyly clohexl]benzoate. Isomers A and B To a solution of the title compound from the previous reaction (50 mg, 0.1 mmol) in 2.5 mL of MeOH and 2 mL of EtOAc was added a catalytic amount of 20% palladium hydroxide on carbon. The reaction was stirred under H2 (balloon) for 5.5 h. The reaction was filtered through celite and the filter cake was washed with EtOAc and MeOH. The combined filtrate and washings were concentrated under reduced pressure to afford the product as a white solid. The cis and trans isomers were separated by HPLC on a ChiralCel OJ column eluting with 10% EtOH/heptane, with Isomer A eluting as the faster moving compound and isomer B as the slower moving compound. Based on 'H NMR 2D NOE analysis, Isomer A is assigned with the trifluoromethyl and 4-hydroxyphenyl groups in a cis configuration and Isomer B is assigned with the trifluoromethyl and 4-hydroxyphenyl groups in a trans configuration. Isomer A: LC-MS (ESI): m/z = 379.26.[M+I] +. 'H NMR (500 MHz, CD 3 OD) 8 7.84 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.9 Hz, 2H), 6.79 (d, J = 8.7 Hz, 2H), 3.85 (s, 3H), 2.79 (d, J = 12.8 Hz, 2H), 2.28 (min, 1H), 1.96 (t, 2H), 1.88 (d, 2H), 1.52 (q, 2H). Isomer B: LC-MS (ESI): m/z= 379.27 [M+1] +. 'H NMR (500 MHz, CD 3 OD) 8 7.98 (d, J= 8.4 Hz, 2H), 7.52 (d, J= 8.5 Hz, 2H14), 7.01 (d, J = 8.7 Hz, 2H), 6.63 (d, J = 8.7 Hz, 2H), 3.89 (s, 3H), 2.86 (d, J= 13.5 H, 2H), 2.29 (min, 1H), 2.00 - 1.89 (overlapping t, d, 4H11), 1.42 (q, 2H). METHOD 2 Step A: 4-l-(4-Hydroxyphenyl)(trifuoromethyl)yclohexl]phenyl trifluoromethanesulfonate To a solution of the title compound of Intermediate 5, Method 1, Step A (1.1 g, 3.2 mmol) in 5 mL of DCM was added pyridine (0.39 mL, 4.8 mmol). After cooling to 0 *C, trifluoromethanesulfonic anhydride (0.55 mL, 3.2 mmol) was added dropwise. After addition the reaction mixture was allowed to stir at ambient temperature for 2 h, then diluted with DCM and poured into 2 N 5 HCI. The organic layer was collected and the aqueous layer was washed twice with DCM. The combined organic layers were dried over Na 2
SO
4 and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel eluting with a gradient of 0% - 40% EtOAc/hexanes over 10 column volumes and 40% - 100% EtOAc/hexanes over 5 column volumes to provide isomer A as the faster moving product and isomer B as the slower eluting product. The bis-triflate 0 product was also isolated. Isomer A: LC-MS (ESI): m/z= 468.06 [M+1] +. 1H NMR (500 MHz, CD 3 OD): 8 7.33 (d, J = 8.9 Hz, 2H1), 7.21 (d, J= 8.7 Hz, 211), 7.17 (d, J= 9 Hz, 21H1), 6.80 (d, J= 8.7 Hz, 2H), 2.77 (d, J = 12.8 Hz, 2H), 2.28 (min, 1H1), 1.96 (t, 2H), 1.89 (br d, 2H), 1.52 (q, 2H). Isomer B: 'H NMR (500 MHz, CD 3 OD): 8 7.53 (d, J= 8.9 Hz, 211), 7.31 (d, J =8.9 Hz, 2H), 7.00 (d, J 5 8.7 Hz, 2H1), 6.65 (d, J = 8.7 Hz, 2H), 2.80 (d, J = 13.3 Hz, 2H1), 2.28 (min, 1H), 1.97 (t, 2H), 1.90 (br d, 2H), 1.41 (q, 2H). -33- WO 2007/111864 PCT/US2007/006806 bis-triflate: LC-MS (ESI): m/z = 617.23. [M+1] +. 'H NMR (500 MHz, CD 3 OD): 8 7.63 (d, J= 8.9 Hz, 2H), 7.40 (overlapping d, d, 4H14), 7.26 (d, I = 9.0 Hz, 2H), 2.91 (br d, J= 13 Hz, 2H), 2.36 (min, 1H), 2.06 (t, 2H), 1.97 (br d, 2H), 1.46 (q, 2H). Step B: Methyl 4-r 1-( 4 -hydroxyphenyl)-4-(trifluoromethyl)cclohexylbenzoate Isomer B To isomer B from the previous reaction (1. I g, 2.4 mmol) in 7 mL of MeOH was added dichloro[1 ,1'-bis(diphenylphosphino)ferrocene]palladium(II), dichloromethane adduct (259 mg, 0.35 mmol) and DIEA (1.7 mL, 9.6 mmol). The reaction was stirred under a CO atmosphere (balloon) at 60 C overnight. The reaction mixture was filtered over celite and the filter cake was washed with MeOH. The combined filtrate and washings were concentrated under reduced pressure. The resulting residue was purified on silica, eluting with a gradient of 0% - 40% EtOAc/hexanes over 10 column volumes and 40% - 100% EtOAc/hexanes over 5 column volumes, affording the title compound as a white solid. LCMS and NMR data for the title compound are consistent with Intermediate 5 Isomer B prepared using Method 1. INTERMEDIATE 6 OH Methyl 4[4-tert-butyl-1-(4-hydroxyphenyl)cyclohexyl1benzoate The title intermediate was prepared from 4-tert-butylcyclohexanone using procedures similar to those described for Intermediate 5, Method 1. LC-MS (ESI): m/z = 367.3 [M+1] . 0 INTERMEDIATE 7, ENANTIOMERS A and B OH
CO
2 Me Step A: Methyl 4(2-hydroxbicyclo2.2. ]hept-2-v)benzoate .5 A solution of methyl 4-iodobenzoate (23.1 g, 0.0882 mol) dissolved in anhydrous THF (200 mL) was cooled to -47 'C. Isopropyl magnesium chloride (48 mL of a 2.0 M solution in THF, 0.097 -34- WO 2007/111864 PCT/US2007/006806 mol) was slowly added to the solution. The reaction mixture was stirred at -47 oC for 1 h, then cannulated into a pre-cooled solution of norcamphor (11.6 g, 0.105 mol) in THF (100 mL) at -47 oC. The reaction mixture was subsequently stirred at -40 oC overnight, and was then allowed to warm to -20 oC. Saturated aqueous ammonium chloride was added. EtOAc was used to extract three times. The combined organic portion was washed with water and brine, dried (MgSO 4 ), filtered, concentrated, and purified by flash chromatography on silica gel (gradient elution; 0% - 30% EtOAc/hexanes as eluent) to afford the title compound. Step B: Methyl 4[2-(4-hydroxvphenyl)bicyclor 2
.
2 .1 lhept-2-vl]benzoate A mixture of phenol (7.80 g, 82.8 mmol) and p-toluenesulfonic acid (2.48 g, 13.0 mmol) in anhydrous toluene (160 mL) was refluxed for 10 min in a 2-neck round bottom flask equipped with a Dean-Stark apparatus. A solution of the title compound from the previous reaction (10.2 g, 41.4 mmol) in toluene (40 mL) was added into the system through an addition funnel over 10 min. The resultant mixture was stirred at reflux for 14 h, then cooled to ambient temperature. The reaction was diluted with EtOAc, washed successively with aqueous sodium hydroxide (IN), water, and brine, dried (MgSO4), filtered, concentrated, and purified by flash chromatography on silica gel (gradient elution; 0% - 20% EtOAc/hexanes) to afford the title compound. Step C: Chiral resolution of methyl 4 [2-(4-hydroxyphenyl)bicyclo[ 2 .2.1 hept-2-vllbenzoate ) The title compound of the previous reaction was resolved into its enantiomeric components by preparative chiral HPLC (Chiralpak AD column, 15% EtOH/heptane as eluent) to provide in order of elution: Enantiomer A, (+) CD deflection, retention time = 9.18 min on analytical Chiralpak AD column (4.6 x 250 mm; 10 micron, flow rate = 1 mL/min, X = 220 nm UV detection); 5 Enantiomer B, (-) CD deflection, retention time = 14.95 min on analytical Chiralpak AD column (4.6 x 250 mm; 10 micron, flow rate = 1 mL/min, X = 220 nm UV detection). Enantiomer B: 'H NMR (500 MHz, CDCl 3 ): 8 9.15 (s, 1H); 7.80 (d, J=8.5 Hz, 2H); 7.43 (d, J=8.5 Hz, 2H); 7.14 (d, J=8.7 Hz, 2H); 6.61 (d, J=8.7 Hz, 2H); 3.79 (s, 3H); 3.29 (s, 1H); 2.18-2.34 (overlapping m, 3H); 1.51 (d, J=9.4 Hz, IH); 1.44 (min, 2H); 1.29 (d, J=9.1 Hz, 1IH); 1.05 (min, 2H). 0 Absolute stereochemical assignments of Enantiomers A and B were established by x-ray crystallography, with Enantiomer A assigned as IS, 2S, 4R and Enantiomer B as 1R, 2R, 4S. -35- WO 2007/111864 PCT/US2007/006806 INTERMEDIATE 8 OH F 3 C
-
I CO 2 Bu Step A: 1-(6-Methox-2-naptclohexanol, Isomers A and B To a cold (-78 'C) anhydrous solution of 2-methoxy-6-bromonaphthelene (1.52 g, 6.40 mmol) in THIF (40 mL) was added n-BuLi (6.9 mL of a 2.5 M solution in hexanes, 6.9 mmol). The mixture was stirred at -78 oC under a nitrogen atmosphere for 15 min, then 4 (trifluoromethyl)cyclohexanone (0.88 g, 5.3 mmol) was added slowly to the reaction mixture. The bath was allowed to warm to room temperature and the reaction mixture was quenched with saturated NH4CI (aq). The resultant mixture was extracted with EtOAc/hexanes. The organic layer was evaporated in vacuo and the crude residue was purified by flash chromatography on silica gel using gradient elution (0% to 20% EtOAc/hexanes, 150 mL; 20% to 35% EtOAc/hexanes, 204 mL; 35% to 75% EtOAc/hexanes, 381 mL) to provide Isomer A as the faster-eluting product and Isomer B as the slower eluting product. Isomer A: IH NMR (500 MHz, CDCI 3 ): 8 7.89 (s, 1 H), 7.80 (t, J = 9.4 Hz, 2 H), 7.64 (d, J= 8.7, 1 H), 7.21 (d, J = 8.9, 1 H), 7.17 (s, 1H), 3.96 (s, 3 H), 2.64-2.52 (min, 2 H), 2.37-2.24 (m, 1 H), 2.15-2.02 (min, 2 H), 1.91-1.80 (min, 2 H), 1.69-1.51 (m, 2 H). Isomer B: 'H NMR (500 MHz, CDCI 3 ): 8 7.89 (s, 1 H), 7.80 (t, J= 9.4 Hz, 2 H), 7.64 (d, J = 8.7 Hz, 1 H), 7.21 (d, J= 8.9 Hz, 1 H), 7.17 (s, 1H), 3.96 (s, 3 H), 2.64-2.52 (m, 2 H), 2.37-2.24 (mn, 1 H), 2.15 2.02 (m, 2 H), 1.91-1.80 (m, 2 H), 1.69-1.51 (m, 2 H). Step B: 4-1-(6-Methoxy-2-naph thyl)-4-(trifloromethyl)cyclohexllphenol, Isomers A and B Isomer A from the previous step (200 ing, 0.61 mmol) and phenol (200 mg, 2.12 mmol) were combined in a 4 mL vial and heated until molten. para-Toluenesulfonic anhydride (80 mg, 0.42 mmol) was then added and the mixture was stirred at 105 C for 30 min. The reaction mixture was 5 allowed to cool to room temperature and diluted with saturated NaHCO 3 (aq). The resultant slurry containing a ca. 1:1 mixture of cis and trans product isomers was extracted with EtOAc. The organic layer was concentrated in vacuo and the residue was purified by flash chromatography on silica gel eluting with a gradient of 20% to 25% EtOAc/hexanes to provide Isomer A as the faster eluting isomer and Isomer B as the slower eluting isomer. 0 Isomer A: LCMS (ESI): m/z = 401.3 [M + H]
+
. 'H NMR (500 MHz, CDCI 3 ): 8 7.69 (d, J= 8.92, 1 H), 7.60 (d, J= 8.7 Hz, 2 H), 7.30-7.23 (min, 3 H), 7.13-7.07 (m, 2 H), 6.84 (d, J = 8.7, 1H), 3.90 (s, 3 H), 2.87 (d, J= 13.2, 2H), 2.30-2.18 (min, 1 H), 2.08-1.92 (m, 4 H), 1.64-1.52 (min, 2 H). - 36 - WO 2007/111864 PCT/US2007/006806 Isomer B: LCMS (ESI): m/z = 401.
3 [M + H]V. IH NMR (500 MHz, CDCl3): 8 7.81 (d, J= 1.6 Hz, 1 H), 7.78(d,J=8.9 Hz, 1 H),7.72(d,J= 8.7Hz, 1 H),7.35(d,J= 8.7Hz, 1 H), 7.20(d, J= 8.9Hz, 1 H), 7.15 (d, J = 2.3 Hz, 1 H), 7.09 (d, J = 8.9, 2H), 6.72 (d, J= 8.9 Hz, 2 H), 3.97 (s, 3 H), 2.89 (d, J = 13.3, 2H11), 2.27-2.16 (in, 1 H), 2.07-1.93 (m, 4 H), 1.74-1.54 (m, 2 H). Ste C: Butyl 4-[(6-methoxy-2-naphthyl)-4-(trifluoromethyl)cyclohexyllbenzoate To a solution of Isomer A from the previous reaction (498 mg, 1.24 mmol) in anhydrous
CH
2
CI
2 (14 mL) were added pyridine (0.15 mL, 1.86 mmol) followed by trifluoromethansulfonic anhydride (1.38 g, 4.89 mmol). The mixture was stirred at room temperature for 20 min, quenched with water, and the resultant mixture was extracted with EtOAc/hexanes. The organic phase was washed with 1N HC1, then passed through a short silica plug. The filtrate was concentrated to dryness to give the crude triflate as a solid. The triflate was taken up in n-butanol (8 mL) and dichloro[1,1' bis(diphenylphosphino)ferrocene]palladium(II), dichloromethane adduct (86 mg, 0.12 mmol) and DIEA (0.61 mL, 3.5 mmol) were added. The reaction mixture was stirred at 90 oC under an atmosphere of CO (balloon) for 1 hour. The resulting mixture was concentrated and purified by flash chromatography on silica gel eluting with a gradient of 25% to 65% EtOAc/hexanes to provide the title compound as solid. LCMS (ESI): nm/z = 485.4 [M + H]
-
. 'H NMR (500 MHz, CDCl 3 ): 8 7.90 (d, J= 8.7 Hz, 2 H), 7.80 (d, J = 1.6 Hz, 1 H), 7.76 (d, J= 8.9 Hz, 1 H), 7.70 (d,J = 8.7 Hz, 1 H), 7.33-7.27 (m, 3 H), 7.19 (dd, J= 8.9, 2.5 Hz, 1 H), 7.13 (d, J = 2.3 Hz, 1 H), 4.29 (t, J= 6.5 Hz, 2 H), 3.94 (s, 3H), 2.93 (d, J = 13.0 Hz, 2 H), S2.28-2.15 (min, 1 H), 2.10-1.94 (min, 4 H), 1.78-1.57 (min, 4H), 1.52-1.41 (min, 2 H), 0.96 (t,J= 7.60 Hz, 3 H). Step D: Butvl 4-[1-(6-hydroxy-2-naphthyl)-4-(trifluoromethyl)cclohexyl]benzoate To a cold (0 'C) solution of the title compound from the previous step (460 mg, 0.95 mmol) in anhydrous CH 2
CI
2 (10 mL) was slowly added BBr 3 (3 mL of a 1.0 M solution in CH 2 C1 2 , 3.0 5 mmol) via syringe under nitrogen. The mixture was stirred at 0 'C for 2 h. The reaction was quenched with water and the resultant mixture was extracted with EtOAc/hexanes. The organic layer was concentrated in vacuo to give the title compound as solid. LC-MS (ESI): m/z = 471.3 [M + H]
+
. 'H NMR (500 MHz, CDCI 3 ): 5 8.05 (d, J = 8.5 Hz, 2 H), 7.73-7.53 (min, 3 H), 7.51 (d, J = 8.5 Hz, 2 H), 7.23-7.06 (min, 3 H), 4.35 (t, J = 6.6 Hz, 2 H), 2.95 (d, J = 12.4 Hz, 2 H), 2.30-2.16 (mn, 1 H), 2.15-1.88 (m, 4 H), 0 1.84-1.69 (m, 2H), 1.68-1.42 (m, 4 H), 1.01 (t, J = 7.32 Hz, 3 H). INTERMEDIATE 9 N OH
CO
2 Bu -37- WO 2007/111864 PCT/US2007/006806 Step A: 1-( 2 -Methoxyquinolin-6- 4trifluormethi)cclohexanol To a cold (-78 'C) anhydrous THF solution of 2-methoxy-6-bromoquinoline (1.16 g, 4.89 mmol) was added n-BuLi (2.05 mL of a 2.5 M solution in hexane, 5.13 mmol). The mixture was stirred at -78 'C under a nitrogen atmosphere for 15 min and 4-(trifluoromethyl)cyclohexanone (0.81 g, 4.89 mmol) was added slowly to the reaction. After addition was complete, the bath was allowed to warm to room temperature. The reaction mixture was quenched with saturated NH 4 CI (aq) and extracted with EtOAc/hexanes. The organic layer was dried over NazSO 4 and evaporated in vacuo and the resultant residue was purified by flash chromatography on silica gel using gradient elution (0% to 20% EtOAc/hexanes, 150 mL; 20% to 35% EtOAc/hexanes, 204 mL; 35% to 75% EtOAc/hexanes, 381 mL) to provide Isomer A as the faster-moving isomer and Isomer B as the slower-moving isomer. Isomer A: LCMS (ESI): m/z = 326.1 [M + H]
+
. 'H NMR (500 MHz, CDCl 3 ): 8 7.99 (d, J= 8.9 Hz, 1 H), 7.87 (d, J = 8.7 Hz, 1 H), 7.83 (d, J = 2.1 Hz, 1 H), 7.75 (dd, J = 8.7, 2.1 Hz,1 H), 6.93 (d,J= 8.7 Hz, 1H), 4.10 (s, 3H), 2.21-2.12 (m, 1 H), 2.05-1.91 (min, 8 H). Isomer B: LCMS (ESI): m/z = 326.2 [M + H]
+
. 'H NMR (500 MHz, CDC1 3 ): 8 7.99 (d, J= 8.7 Hz, 1 H), 7.89 (d, J = 8.7 Hz, 1 H), 7.82-7.76 (m, 2 H), 6.94 (d, J= 8.7 Hz, 1 H), 4.10 (s, 3H), 2.58-2.49 (m, 2 H), 2.36-2.24 (m, 1 H), 2.13-2.03 (m, 2 H), 1.89-1.78 (min, 2 H), 1.67-1.57 (m, 2 H). Step B: 4- (2Methoxvquinolin-6-vl)-4-(trifluoromethvl)cclhexvlpenl Isomer A To phenol (0.46 g, 4.9 mmol) dissolved in trifluoromethanesulfonic acid (3 mL) was added Isomer A from the previous step (1.06 g, 3.26 mmol). The mixture was stirred at room temperature for 16 h, then transferred to an ice/water bath and quenched by slow addition of saturated aqueous NaHCO 3 . The resulting mixture containing two product isomers was extracted with EtOAc. The organic phase was evaporated in vacuo to provide a solid residue which was triturated with toluene/DCM (1:3 v/v). The slurry was filtered through a fritted funnel and the filter cake was washed with DCM (2x) and S toluene (2x). Isomer A, which provided the more potent glucagon receptor antagonists I, remained in the filter cake while Isomer B passed into the filtrate. Isomer A was dissolved in EtOAc and washed with 1 N HCI (aq) and brine. The organic phase was concentrated to provide title Isomer A as a white solid. LCMS (ESI): m/z 402.2 [M + H]. D Step C: Butvl 4[(2-methoxyquinolin-6y)-4-(trifluoromethyl)cyclohexbenzoate To a solution of Isomer A from the previous step (800 mg, 1.99 mmol) in anhydrous
CH
2 Cl 2 (10 mL) were added pyridine (0.24 mL, 3.0 mmol) and trifluoromethanesulfonic anhydride (0.40 mL, 2.4 mmol). The mixture was stirred at room temperature for 20 min, then quenched with water and extracted with EtOAc/hexanes. The combined organic phase was washed with H 2 0 (2x), then brine. The 5 organic phase was dried over Na 2 SO4 and passed through a short silica plug. The eluent was concentrated to dryness to give the crude triflate. A portion of the triflate (875 mg, 1.64 mmol) was taken up in n butanol (12 mL) and PdCl 2 (dppf), dichloromethane adduct (120 mg, 0.1 mmol) and DIEA (0.86 mL, 3 -38- WO 2007/111864 PCT/US2007/006806 mmol) were added. The resulting slurry was stirred at 90 oC under a CO atmosphere (balloon) for 1 h. The reaction mixture was concentrated and purified by flash chromatography on silica gel eluting with a gradient of 16% to 50% EtOAc/hexanes to provide the title compound. LCMS (ESI): m/z = 486.2 [M +
H]
+
. H NMR (500 MHz, CDCl 3 ): 8 8.07 (d, J = 8.5 Hz, 2 H), 7.92 (d, J= 8.9 Hz, 1 H), 7.74 (d, J = 8.9 Hz, 1 H), 7.54-7.49 (in, 3 H), 7.44 (dd, J = 8.9, 2.3 Hz, 1 H), 6.91 (d, J= 8.9 Hz, 1 H), 4.36 (t, J= 6.6 Hz, 2 H), 4.07 (s, 3H), 2.95 (d, J = 13.4 Hz, 2 H), 2.3-2.19 (min, 1 H), 2.15-1.97 (min, 4 H), 1.79 (quint, J 6.6 Hz, 2 H), 1.66-1.47 (min, 4 H), 1.02 (t, J = 7.3 Hz, 3 H). Step D: Butyl 4-[l-( 2 -hydroxvoxqui oli-6)(trifluoromethyl)cyclohexvl]benzoate To a stirring solution of the title compound from the previous step (490 mg, 1.0 mmol) in anhydrous dichloroethane (5 mL) was slowly added trimethylsilyl iodide (0.82 mL, 5.7 mmol). The mixture was stirred at 65 'C for 3.5 h, then the reaction mixture was concentrated in vacuo. The residue was reconcentrated in vacuo first from toluene (20 mL), then from a mixture of 2-propanol (6 mL) and toluene (10 mL) to provide the title compound. LC-MS (ESI): m/z = 472.2 [M+1] +. 'H NMIR (500 MHz,
CDCI
3 ): 8 8.08 (d, J = 8.2 Hz, 3 H), 7.63-7.50 (min, 3 H), 7.49 (d, J = 8.2 Hz, 2 H), 6.94 (d, J = 9.4 Hz, 1 H), 4.36 (t, J= 6.6 Hz, 2 H), 2.92 (d, J= 13.0 Hz, 2 H), 2.31-2.18 (min, 1 H), 2.15-1.97 (min, 4 H), 1.83 1.71 (min, 2 H), 1.65-1.46 (min, 4 H), 1.01 (t, J= 7.3 Hz, 3 H). INTERMEDIATE 10 SN OH FzC CO 2 Bu Step A: 1-(6-Methoxpyridin-3-yl) 4-(trifluoromethyl)gyclohexanol n-Butyllithium (3 mL of a 2.5 M solution in hexanes, 7.5 mmol) was added dropwise to 5-bromo-2-methoxy pyridine (6.0 mmol, 0.78 mL) in 40 mL of THF cooled in a dry ice/acetone bath. After aging for 15 min, 4-trifluoromethylcyclohexanone (6.0 mmol, 1 g) was added and the reaction 5 mixture was allowed to slowly warm to 0 oC over 2h. The reaction was cooled in a dry ice/acetone bath and the reaction was quenched by addition of sat. ammonium chloride (aq), then saturated sodium bicarbonate (aq). The reaction mixture was extracted with hexanes/EtOAc. The organic phase was concentrated and the resultant residue was purified by flash chromatography on silica gel using a step gradient of 4:1, 2:1 and 1:1 (v/v) EtOAc/hexanes to give the title compound as a mixture of isomers. LC 0 MS (ESI): m/z = 276.2 [M+1] . -39- WO 2007/111864 PCT/US2007/006806 Step B: 4-[1-(6-Methoxypyridin-3-vl)-4-(trifluoromethyl)cyclohexy1 plenol Step B: 4-l(-ehxgyIe1peo To solution of phenol (680 mg, 7.2 mmol) in 3 inL of trifluoromethanesulfonic acid was added the title compound of the previous step (1.15 g, 4.2 mmol). The reaction was slightly exothermic and the mixture was cooled in an acetone bath. After 1.5 h, the reaction mixture was poured into saturated sodium bicarbonate (aq) and extracted with twice with EtOAc. The organic phase was concentrated and the resultant residue was purified by flash chromatography on silica gel eluting with a gradient of 10% to 20% EtOAc/hexanes to give the title compound as a mixture of two isomers. LC-MS (ESI): m/z = 35 2
.
3 [M+1] +. Step C: Butyl 4-[ 1-(6-methoxvpyridin- 3 .vl)-4-(trifluoromethyl)cyclohexylbenzoate To the title compound of the previous reaction (1.3 g, 3.6 mmol) and pyridine (0.42 mL, 5.2 mmol) in 30 mL of dichloromethane was added dropwise trifluoromethanesulfonic anhydride (0.65 mL, 3.9 mmol). The reaction mixture was partitioned between aqueous sodium bicarbonate/hexanes EtOAc. The organic phase was separated, washed with water, dried over sodium sulfate, then passed through a plug of silica gel and concentrated. The crude triflate was taken up in 20 mL of n-butanol, and PdCI 2 (dppf),dichloromethane adduct (250 mg, 0.3 mmol) and DIEA (0.9 mL, 5.2 mmol) were added. The reaction was stirred at 90 oC under CO (balloon) for 2 h and the reaction was concentrated in vacuo. Flash chromatography on silica gel eluting with 15 % EtOAc/hexanes provided the title compound as a mixture of two isomers. LC-MS (ESI): m/z= 436.4 [M+1] . Step D: Butvl 4-1(6-hydroxyridin-3-yl)-4-(trifluoromethyl)cyclohexylbenzate To a solution of the title compound from the previous step (1.4 g, 3.3 mmol) in dichloroethane (12 mL) was added 2 mL oftrimethylsilyl iodide. The reaction mixture was heated at 55 oC for 6 h. The solvent was removed in vacuo. The residue was concentrated first from toluene, then 5 from a mixture oftoluene/isopropyl alcohol. Flash chromatography on silica gel eluting with a gradient of 33% to 50% EtOAc/hexanes provided Isomer A as the faster-eluting compound and Isomer B as the slower-eluting compound. Isomer A: iH NMNR (500 MHz, CD 2 Cl 2 ): 8 (ppm) 7.95 (d, J= 8.5 Hz, 2H), 7.81 (s, 1H), 7.33 (d, J= 8.5 Hz, 2H), 6.73 (d, J= 9.2 Hz, 111), 4.29 (t, J= 6.5 Hz, 2H), 2.65 (d, J= 13.0 Hz, 2H), 2.25 (min, 1H), 1.74 0 (m, 2H1), 0.98 (t, J= 7.4 Hz, 3H11). Isomer B: 'H NMR (500 MH-Iz, CD 2 C1 2 ): 5 (ppm) 8.06 (d, J= 8.2 Hz, 2H), 7.64 (d, J= 2.3 Hz, 1H), 7.48 (min, 3H1), 6.67 (d, J= 9.4 Hz, 111), 4.33 (t, J= 6.6 Hz, 2H-I), 2.79 (d, J= 13.0 Hz, 2H), 2.25 (mn, 1H11), 1.77 (min, 2H), 1.00 (t, J= 7.4 Hz, 3H). -40 - WO 2007/111864 PCT/US2007/006806 EXAMPLE 1
F
8 C 00 O N' OH H Step A: 4- 1-[4-(Benzyloxy)phenyl]-4-(trifluoromethyl)cyclohexvlbenzoic acid To the title compound of Intermediate 5, Method 1, Step D (11.5 mg, 0.02 mmol) in 1 mL of dioxane was added a solution of LiOH (7 mg, 0.3 mmol) in 0.5 mL of water. The reaction was stirred at room temperature for 16 h. The reaction mixture was taken up in aqueous pH 7 buffer and extracted with EtOAc. The organic layer was collected and the aqueous layer was washed twice with EtOAc. The combined organic phase was concentrated under reduced pressure. LC-MS (ESI): m/z = 455.2 [M+1] +. Step B: 3-( 4-[-4-(Benzyloxy)phenyll-4-(triflurmethyl)ylheybenz amino)propanoic acid To a solution of the title compound of the previous step (5.9 mg, 0.012 mmol), j3-alanine tert-butyl ester hydrochloride (5 mg, 0.03 mmol), HOBt (5 mg, 0.03 mmol) and EDC (6 mg, 0.03 mmol) ; in 0.5 mL of DMF was added DIEA (0.007 mL, 0.04 mmol). The reaction was heated to 45 'C for I h, then partitioned between EtOAc/water. The organic layer was collected and the aqueous layer was washed twice with EtOAc. The combined organic phase was concentrated under reduced pressure. LC MS (ESI): m/z= 582.3 [M+1] 4 . The resultant residue was dissolved in 1 mL of DCM containing 0.015 mL of water and ) 0.60 mL oftrifluoroacetic acid was added. The reaction was stirred at room temperature for 50 min. The solvent was removed and the residue was purified by reverse-phase chromatography (35%-100% MeCN/H20, both containing 0.1 % TFA) to provide the title compound as a 1.6:1 mixture of stereoisomers. LC-MS (ESI): m/z = 526.1 [M+I] +. Major isomer: 'H NMR (500 MHz, CD 3 OD): 5 7.65 (d, J = 8.4 Hz, 2H), 7.48 (d, J= 7.6 Hz, 2H), 7.39 5 7.29 (overlapping m, 3H), 7.33 (d, J = 8.9 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 7.01 (d, J= 8.9 Hz, 21-1), 5.08 (s, 21H), 3.59 (t, 2H), 2.83 (br d, J = 13 Hz, 2H), 2.61 (t, 2H), 2.30 (m, 1H), 1.99 (t, 2H-1), 1.91 (br d, 2H), 1.53 (q, 2H). Minor isomer: 8 7.78 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H), 7.39 - 7.29 (overlapping m, 5H), 7.12 (d, J = 8.9 Hz, 2H), 6.84 (d, J = 9 Hz, 2H), 5.01 (s, 2H), 3.63 (t, 21-1), 2.87 (br d, J = 14 Hz, 2H), 2.64 (t, 2H), 2.30 (m, 1H), 1.99 (t, 2H), 1.91 (br d, 2H), 1.48 (q, 2H). 0 -41- WO 2007/111864 PCT/US2007/006806 EXAMPLE 2
F
3 C - .. ~~i~F 0 O OH Step A: Methyl 4-f1- 4-f(3.fluorobenl)OXyphenyll-4-(trifluoromethyl)cylohexyl1benzoate To a solution of Intermediate 5, Isomer B (20 mg, 0.05 mmol) in 1 mL of DMF was added CszCO 3 (58 mg, 0.15 mmol) and 3-fluorobenzyl bromide (0.019 mL, 0.15 mmol). The reaction mixture was stirred at 40 'C for 2 h, then at ambient temperature for 16 h. The reaction was partitioned between EtOAc and saturated aqueous NaHCO 3 . The organic layer was collected and the aqueous layer was washed twice with EtOAc. The combined organic layers were concentrated under reduced pressure. LC-MS (ESI): m/z = 487.3 [M+1] *. Step B: 4-[lf4_f(3_Fluorobenzyl)oxv]phenyll-4-(trifluoromethyl)cclohexyllbenzoic acid To the title compound from the previous step (0.05 mmol) in 1 mL of dioxane was added a solution of LiOH (10 mg, 0.41 mmol) in 0.5 mL of water. The reaction was stirred at 40 'C for 2 h and at room temperature for 16 h. The reaction mixture was partitioned between aqueous pH 7 buffer and ; EtOAc. The organic layer was collected and the aqueous layer was washed twice with EtOAc. The combined organic layers were dried over Na 2 SO4 and concentrated under reduced pressure to provide the title compound as a white solid. LC-MS (ESI): m/z = 473.3 [M+I]
+
. Step C: 3( 4j 1- f 4-f(3 Fluorobenzyl)ox¥]phenl} -4-(trifluoromethyl)eyclohexml benzoyl}amino)propanoic acid To a solution of the title compound from the previous step (35mg, 0.05mmol), (3-alanine ethyl ester hydrochloride (18 mg, 0.1 mmol), HOBt (15 mg, 0.1 mmol) and EDC (19 mg, 0.1 mmol) in 1 mL of DMF was added DIEA (0.026 mL, 0.15 mmol). The reaction mixture was heated to 40 'C for 2 h, then partitioned between EtOAc/brine. The organic layer was collected and the aqueous layer was 5 washed twice with EtOAc. The combined organic layers were concentrated under reduced pressure to provide the crude ester. LC-MS (ESI): m/z = 600.4 [M+1] +. The resultant residue was dissolved in 0.70 mL of DCM with 0.015 mL of water and 0.50 mL of trifluoroacetic acid. The reaction mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and the product was purified by reverse-phase chromatography (50 0 100% MeCN/IH 2 0, both containing 0.1% TFA). Lyophilization provided the title compound as a white solid. -42- WO 2007/111864 PCT/US2007/006806 LC-MS (ESI): m/z= 544.3 [M+1]
+
. IH NMR (500 MHz, CD 3 OD): 8 7.77 (d, J = 8.5 Hz, 2H), 7.50 (d, J 8.5, 2H), 7.35 (m, 11), 7.19 (d, J= 7.8 Hz, 1H), 7.12 (overlapping d, m, 3H), 7.00 (t, 1H), 6.83 (d, J = 8.9 Hz, 2H), 5.02 (s, 21H), 3.62 (t, 21), 2.86 (d, J = 13.3 Hz, 2H), 2.63 (t, 2H), 2.29 (m, 1H), 1.98 (t, 2H), 1.91 (br d, 2H), 1.44 (q, 2H). EXAMPLE 3
SOCF
3
F
3 C 0 0 N ' OH H Step A: Methyl 4-[4-(trifluoromethyl)- (4- r(trifluoromethyl)sulfonvlloxV}phenyl)cyclohexyllbenzoate To a solution of Intermediate 5, Isomer B (120 mg, 0.32 mmol) and pyridine (0.13 mL, 1.6 mmol) in 2 mL of DCM was added trifluoromethanesulfonic anhydride (0.11 mL, 0.63 mmol). The reaction mixture was allowed to stand at ambient temperature for 1 h, then diluted with DCM and poured into 2 N HC1. The organic layer was collected and the aqueous layer was washed twice with DCM. The combined organic layers were dried over Na 2
SO
4 and concentrated under reduced pressure to provide the title compound as a yellow solid. LC-MS (ESI): m/z= 511.2 [M+l1] . 'H NMR (500 MHz, CD 3 OD): 8 8.02 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 9.1 Hz, 2H), 7.22 (d, J = 9 Hz, 2H), 3.89 (s, 3H), 2.93 (d, J = 13.1 Hz, 2H), 2.33 (m, 1H), 2.03 (t, 2H14), 1.94 (br d, 2H1), 1.45 (q, 2H). Step B: 4-[ l-4'-(Trifluoromethox)biphel4l4(trfluoromethyl)cyclohexyvll]benzoic acid To a mixture of the title compound from the previous step (8 mg, 0.016 mmol), 4 ) (trifluoromethoxy)benzeneboronic acid (4.8 mg, 0.024 mmol) and tetrakis(triphenyl phosphine)palladium(0) (1.8 mg, 0.0016 mmol) was added 0.40 mL of ethylene glycol dimethyl ether, 0.20 mL of ethanol and 0.20 mL of 2M sodium carbonate (aq). The reaction mixture was heated in a CEM Discover microwave reactor at 150*C for 10 min. The reaction mixture was partitioned between DCM and saturated aqueous NaHCO 3 . The organic layer was collected and the aqueous layer was washed 5 twice with DCM. The combined organic phase was concentrated under reduced pressure then purified by reverse phase chromatography (65%-100% MeCN/water, both containing 0.1 % TFA) to provide the title compound. LC-MS (ESI): m/z = 509.3 [M+1] . -43 - WO 2007/111864 PCT/US2007/006806 Step C: tert-Butvl 3-(4-[1 -[ 4 '-(trifluoromethoxy)biphenyv1-4yl-4-(trifluoromethyl) cyclohexvl]benzoyal amino)propanoate To a solution of the title compound from the previous step (25 mg, 0.05 mmol), P-alanine tert-butyl ester hydrochloride (24 mg, 0.13 mmol), HOBt (20 mg, 0.13 mmol) and EDC (25 mg, 0.13 mmol) in 1 mL of DMF was added DIEA (0.035 mL, 0.2 mmol). The reaction mixture was heated at 40 C for 1.5 h, then partitioned between EtOAc/brine. The organic layer was collected and the aqueous layer was washed twice with EtOAc. The combined organic layers were dried over Na 2
SO
4 and concentrated under reduced pressure to afford the title compound as an amber oil. LC-MS (ESI): m/z = 636.4 [M+1] . Step D: 3-({4.[1-4'-(trifluoromethoxy)biphenyl-4-yl]-4-(trifluoromethyl)cyclohexi benzoyl}amino) propanoic acid The title compound from the previous step (0.05 mmol) was taken up in 0.70 mL of DCM and 0.015 mL of water with 0.50 mL of trifluoroacetic acid. The reaction was stirred at room temperature for 1 h. The reaction was concentrated in vacuo and the residue was purified by reverse phase chromatography (60%-100% MeCN/H 2 0, both containing 0.1 % TFA). Lyophilization afforded the title compound as a white solid. LC-MS (ESI): m/z = 580.3 [M+1] ]. 1H NMR (500 MHz, CD 3 OD): 8 7.80 (d, J = 8.5 Hz, 2H1), 7.63 (d, J= 8.7 Hz, 2H), 7.56 (d, J = 8.5 Hz, 2H), 7.49 (d, J= 8.4, 2H), 7.32 7.29 (overlapping d, d, 4H), 3.62 (t, 2H), 2.95 (d, J = 14 Hz, 2H), 2.63 (t, 2H1), 2.34 (m, 1H1), 2.06 (t, 2H), 1.95 (d, 2H), 1.49 (q, 2H). EXAMPLE 4 C1
F
3 C CF 3 0 0 N'>kOH H Step A: 4-r[1 -( 4 Hydroxvphenvl)-4-(trifluoromethyl)cyclohexyllbenzoic acid To Intermediate 5, Isomer B (172 mg, 0.45 mmol) in 1 mL of dioxane was added a solution of LiOH (44 mg, 1.8 mmol) in 0.5 mL of water. The reaction was stirred at 45 'C for 2 h. The 5 reaction mixture was taken up in aqueous pH 7 buffer and extracted with EtOAc. The aqueous layer was washed twice with EtOAc and the combined organic layers were concentrated under reduced pressure to provide the title compound as an off-white solid. LC-MS (ESI, neg. ion): m/z = 363.2 [M-1] -. 'H NMR (500 MHz, CD 3 OD): 8 7.99 (d, J = 8.5 Hz, 2H1), 7.51 (d, J= 8.5 Hz, 2H1), 7.02 (d, J = 8.7 Hz, 2H), 6.64 (d, J = 8.7 Hz, 2H11), 2.86 (d, J = 13.5 Hz, 2H1), 2.29 (m, 1H), 2.00 - 1.90 (overlapping t, d, 4H), 1.44 (q, 2H1). 0 Step B: tert-Butvl 3(4 (4-hydrox nyl)-4-(trifluoromethyl) lhexyllbenzol amino) propanoate -44 - WO 2007/111864 PCT/US2007/006806 To a solution of the title compound from the previous step (0.6 mmol), -alanine tert butyl ester hydrochloride (221 mg, 1.2 mmol), HOBt (184 mg, 1.2 mmol) and EDC (230 mg, 1.2 mmol) in 3 mL of DMF was added DIEA (0.32 mL, 1.8 mmol). The reaction was heated at 40 *C for 2 h, then partitioned between EtOAc/brine. The organic layer was collected and the aqueous layer was washed 2 times with EtOAc. The combined organic layers were concentrated under reduced pressure. Flash chromatography on silica gel eluting with a gradient of 0% - 40% EtOAc/hexanes over 10 column volumes, then 40 - 100% EtOAc/hexanes over 5 column volumes provided the title compound. LC-MS (ESI): m/z = 436.4 [M+1]
+
. 'IH NMR (500 MHz, CD 3 OD): 8 7.76 (d, J = 8.5 Hz, 2H1), 7.49 (d, J = 8.5 Hz, 2H), 7.01 (d, J = 8.9 Hz, 2H), 6.62 (d, J= 8.6 Hz, 2H11), 3.59 (t, 2H), 2.84 (d, J = 13.5 Hz, 2H), 2.56 (t, 211), 2.29 (m, 1H), 1.96 - 1.87 (overlapping t, d, 4H1), 1.44 (s, 9H1). Step C: tert-Butvl 3-({4-f4-(trifluoromethy)--(4-{[(trifluoromethyl)sulfonylloxvphen¥)gcvoexylI benzov1} amino)propanoate A solution of the title compound from the previous step (263mg, 0.54 mmol) and pyridine (0.13 mL, 1.6 mmol) in 5 mL of DCM was cooled to -78°C. Trifluoromethanesulfonic anhydride (0.14 mL, 0.8 mmol) was slowly added to the reaction mixture. The reaction mixture was allowed to warm to ambient temperature and stirred for 0.5 h, then diluted with DCM and poured into 2 N HCI (aq). The organic layer was collected and the aqueous layer was washed twice with DCM. The combined organic layers were dried over Na 2 SO4 and concentrated under reduced pressure. ) Lyophilization from benzene provided the title compound as an off-white solid. LC-MS (ESI): m/z = 568.3 [M+l]
+
. 'H NMR (500 MHz, CD 3 OD): 8 7.80 (d, J = 8.5 Hz, 2H11), 7.55 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 9 Hz, 2H11), 7.21 (d, J = 8.9 Hz, 2H), 3.59 (t, 2H), 2.92 (d, J = 13.5 Hz, 2H11), 2.56 (t, 2H11), 2.33 (min, 1H), 2.02 (t, 2H1), 1.94 (br d, 2H), 1.43 (s, 9H). 5 Step D: 3-({4-f1-[4'-Chloro-3'-(trif l u oromethyl)biphen y l- 4vl
]
-
4- (trifluorometh y l
)
cy clohex y l benzovl}amino)propanoic acid To a mixture of the title compound from the previous step (15 mg, 0.03 mmol), 4-chloro 3-(trifluoromethyl)phenylboronic acid (10 mg, 0.045 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.5 mg, 0.003 mmol) was added 0.50 mL of ethylene glycol dimethyl ether and 0.010 mL of 0 triethylamine. The reaction mixture was heated in a CEM Discover microwave reactor at 150 'C for 20 minutes. After cooling to ambient temperature, the reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO 3 and the aqueous layer was washed twice with EtOAc. The combined organic phase was concentrated under reduced pressure. LC-MS (ESI): m/z = 654.2 (M+1). The residue was dissolved in 0.70 mL of DCM with 0.015 mL of water and 0.50 mL of trifluoroacetic acid. The reaction 5 was stirred at room temperature for I h. The solvent was removed and the product was purified by reverse phase chromatography (50-100% MeCN/H 2 0, both containing 0.1 % TFA). Lyophilization afforded the title compound as a white solid. LC-MS (ESI): m/z = 598.4 [M+1]
+
. IH NMR (500 MHz, - 45 - WO 2007/111864 PCT/US2007/006806
CD
3 OD): 8 7.91 (s, 1H1), 7.82 - 7.78 (overlapping d, d, 3H), 7.64 (d, J = 8.2 Hz, 11H), 7.57 (d, J= 8.4 Hz, 2H), 7.53 (d, J= 8.7 Hz, 2H), 7.37 (d, J= 8.6 Hz, 2H), 3.63 (t, 2H), 2.96 (d, J= 13.3 Hz, 2H11), 2.64 (t, 2H), 2.34 (min, 1H), 2.06 (t, 2H), 1.96 (br d, 21H), 1.49 (q, 2H). EXAMPLE 5
F
3 F FC 0 O 0 O N ' OH H Step A: Ethyl 3-( {4-1-( 4 -hydroxvphenyl)-4-(trifluoromethyl)cyclohexyllbenzovyl amino)propanoate To a solution of the title compound of Example 4, Step A (43mg, 0.09 mmol), j-alanine ethyl ester hydrochloride (28 mg, 0.18 mmol), HOBt (28 mg, 0.18 mmol) and EDC (35 mg, 0.18 mmol) in 1 mL of DMF was added DIEA (0.047 mL, 0.27 mmol). The reaction was heated at 50 *C for 1.5 h, then partitioned between EtOAc/brine. The organic layer was collected and the aqueous layer was washed twice with EtOAc. The combined organic phase was concentrated under reduced pressure to provide the title compound. LC-MS (ESI): m/z = 464.3 [M+I] +. S Step B: Ethyl 3-({4-f4--(4f(4-fluorobenzvyl)oxvyphenl -4-(trifluoromethyl)cvclohexyl]benzoyl amino) propanoate To a solution of the title compound from the previous step (8.7 mg, 0.02 mmol) in 0.5 mL of DMF was added Cs 2 CO3 (17 mg, 0.045 rnmol) then 4-fluorobenzyl bromide (0.0056 mL, 0.045 mmol). The reaction was stirred at 40 °C for 1 h, then allowed to stir at ambient temperature. The reaction was partitioned between EtOAc and saturated aqueous NaHCO 3 . The organic layer was collected and the aqueous layer was washed 2 times with EtOAc. The combined organic layers were concentrated under reduced pressure to provide the title compound. LC-MS (ESI): m/z = 572.3 [M+l] . Step C: 3-(f4-r l-4-r( 4 -Fluorobenzyl)oxyVphenyl1-4!-(trifluoromethyl)cyclohexyl]benzoylI amino) 5 propanoic acid To a solution the title compound from the previous step (11 mg, 0.02 mmol) in 0.80 mL of dioxane was added a solution of LiOH (5 mg, 0.2 mmol) in 0.40 mL of water. The reaction was stirred at 40 *C for 1 h, then left stirring at room temperature overnight. The reaction mixture was acidified with 0.050 mL oftrifluoroacetic acid and purified by reverse phase chromatography (50% - 100% MeCN/H 2 0, 0 both containing 0.1 % TFA). Lyophilization afforded the title compound as a white solid. LC-MS (ESI): -46- WO 2007/111864 PCT/US2007/006806 m/z = 544.3 [M+I] . 'H NMR (500 MHz, CD 3 OD): 8 7.77 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 7.40 (m, 2H), 7.11 (d, J = 8.9 Hz, 2H), 7.06 (dd, J= 8.8 Hz, 8.8 Hz, 2H), 6.83 (d, J= 8.7 Hz, 2H), 4.98 (s, 2H), 3.62 (t, 2H), 2.86 (d, J = 13.7 Hz, 2H), 2.61 (t, 2H), 2.29 (min, 1H), 1.98 (t, 2H), 1.90 (br d, 2H1), 1.44 (q, 2H). EXAMPLE 6 F3C 0 O N-"-0H H Step A: Methyl 4-rl-[4-(3,4-dihvdroquinolin-1( 2 H)1vl)phenvll-4-(trifluoromethyl)cyvclohexvl]benzoate To a mixture of the title compound of Example 3, Step A (50 mg, 0.1 mmol), 1,2,3,4 tetrahydroquinoline (0.019 mL, 0.15 mmol), 2-(di-tert-butylphosphino)biphenyl (1 mg, 0.003 mmol), palladium (II) acetate (0.5 mg, 0.002 mmol) and sodium tert-butoxide (13 mg, 0.14 mmol) was added 0.30 mL of toluene. The reaction was stirred at 90 0 C for 16 h, then partitioned between EtOAc/brine acidified with a few drops of 2 N HCI. The aqueous layer was washed with EtOAc then DCM. The combined organic layers were concentrated under reduced pressure to provide the product as a mixture of S the title methyl ester and the hydrolyzed carboxylic acid. LC-MS (ESI): m/z = 494.3 [M+1] '. Step B: 4-41-[4-(3,4-Dihydroquinolin-l( 2
H)
-
vl ) p henvll - 4 -(trifluoromethyl)cyclohexv l] benzoic acid To the title compound from the previous step (49 mg, 0.1 mmol) in 1 mL of dioxane was added a solution of LiOH (10 mg, 0.41 mmol) in 0.5 mL of water. The reaction was stirred at 40 *C. ) The reaction mixture was acidified with a few drops trifluoroacetic acid, then partitioned between aqueous pH 7 buffer and EtOAc. The aqueous layer was washed twice with EtOAc and the combined organic phase was concentrated under reduced pressure. Reverse phase chromatography (55% - 100% MeCN/H 2 0, both containing 0.1 % TFA) provided the title compound. LC-MS (ESI): m/z = 480.3 [M+1] +. 5 Step C: 3-({4-[1-r4-(3,4-Dihydroquinolin- 2 ) v l) h e n l - 4 - (tr f l u r m eth y l) y cl h x b e n z amino)propanoic acid To a solution of the title compound from the previous step (0.1 mmol), 3-alanine tert butyl ester hydrochloride (36 mg, 0.2 mmol), HOBt (31 mg, 0.2 mmol) and EDC (38 ing, 0.2 mmol) in 1 0 mL of DMF was added DIEA (0.052 mL, 0.3 mmol). The reaction was allowed to stand at room - 47 - WO 2007/111864 PCT/US2007/006806 temperature for 16 h, then partitioned between EtOAc/brine. The organic layer was collected and the aqueous layer was washed twice with EtOAc. The combined organic phase was concentrated under reduced pressure. LC-MS (ESI): m/z = 607.3 [M+1] +. The resultant residue was dissolved in 0.70 mL of DCM with 0.015 mL of water and 0.50 mL of trifluoroacetic acid. The reaction was stirred at room 5 temperature for 1 h. The solvent was removed and the product was purified by reverse phase chromatography (10% - 100% MeCN/H 2 0, both containing 0.1% TFA). Lyophilization afforded the title compound as a beige solid. LC-MS (ESI): m/z = 551.5 [M+I1] +. 'H NMR (500 MHz, CD 3 OD) 8 7.79 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H), 7.18 (d, J = 8.7 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 6.96 (d, J = 7.8 Hz, IH), 6.80 (t, 1H), 6.60 (t, 1H), 6.54 (d, J = 8.5 Hz, IH), 3.62 (t, 2H), 3.52 (t, 2H), 2.91 (d, J = 13.7 0 Hz, 2H), 2.77 (t, 21), 2.63 (t, 2-1), 2.32 (m, 11), 2.05-1.91 (overlapping, t, d, mn, 6H),1.48 (q, 2H). EXAMPLE 7 CI
F
3 C 0"O CI 0 I ~OH 0 N >kOH H Step A: Methyl 4-r[1-(3,5-dichloro-4-hydroxyphenyl)-4-(trifluoromethyl)cyclohexl]benzoate 5 Intermediate 5, Isomer B (0.26 mmol, 100 mg) was taken up in S0 2 Cl 2 (1 mL) in a 10 mL roundbottom flask fitted with a rubber septum and syringe needle (gas evolution). The resultant solution was heated at 50 oC for 16 h. The reaction was concentrated in vacuo and the residue was purified by preparative TLC on silica eluting with 15% EtOAc/hexanes to provide the title compound as an amber solid. LC-MS (ESI): m/z = 447.0 [M+1] +, 449.0 [M+3] +. ) Step B: Methyl 44- -{3,5-dichloro-4-r(cyclohexylmethyl)oxy]phenvll-4-(trifluoromethyl)cyclohexyll benzoate A slurry of the title compound from the previous step (0.08 mmol, 37 mg), bromomethylcyclohexane (0.25 mmol, 0.035 mL) and Cs 2
CO
3 (0.25 mmol, 81 mg) in DMF (1 mL) was 5 stirred at 60 C for 4 h. The reaction mixture was partitioned between DCM/brine. The organic phase was dried over Na 2
SO
4 and concentrated, then taken directly to the next step. - 48 - WO 2007/111864 PCT/US2007/006806 Step C: N-({ 4-Fl-{3,5-Dichloro- 4 -f(cyclohexylmethyl)ox]phenvl-4-(trifluoromethl)evlohexyl phenyl } carbonvl)-3-alanine To the title compound from the previous step in 2 mL of dioxane was added a solution of LiOH (1 mmol, 24 mg) in 1 mL of H20. The resulting solution was stirred at 40 oC for 1 h, then 5 partitioned between DCM/1N HCI (aq). The organic phase was dried over Na 2
SO
4 and concentrated in vacuo. The residue was taken up in DMF (1 mL) and 3-alanine ethyl ester hydrochloride (0.2 mmol, 31 mg), EDC (0.2 mmol, 38 mg) and HOBt (0.2 mmol, 31 mg) were added, followed by DIEA (0.3 mmol, 0.052 mL). The reaction mixture was heated at 40 oC for 2 h, then partitioned between DCM/brine. The organic phase was concentrated in vacuo and the resulting residue was taken up in 2 mL of dioxane. A 0 solution of LiOH (1 mmol, 24 mg) in 1 mL of H20 was added and the resulting solution was stirred at 40 'C for 2 h. The reaction was acidified by addition of TFA (0.10 mL), then purified by reverse phase HPLC (60% - 100% MeCN/H 2 0, both containing 0. 1% TFA). Lyophilization provided the title compound as a white solid. 'H NMR (500 MHz, d 6 -DMSO) 8 12.18 (br s, 1H); 8.50 (t, J = 5.5 Hz, 1H); 7.78 (d, J = 8.4 Hz, 2H); 7.54 (d, J= 8.4 Hz, 2H); 7.25 (s, 2H1); 3.68 (d, J= 6.2 Hz, 2H); 3.36-3.50 Hz 5 (overlapping m, 4H1); 2.90 (d, J=13.1 Hz, 2H); 2.43 (m, 111); 1.89 (min, 2H); 1.57-1.85 (overlapping m, 8H); 1.00-1.28 (overlapping m, 7H1). EXAMPLE 8 F3C 0 O N' OH H ) Step A: Methyl 4-fl-( 4 -hydroxy- 3 -iodophenyl)-4-(trifluoromethyl)cyclohexyl1benzoate To a solution of Intermediate 5, Isomer B (220 mg, 0.58 mmol) and calcium carbonate (58 mg, 0.58 mmol) in 1.5 mL of MeOH and 0.5 mL of DCM was added benzyltrimethylammonium dichloroiodate (202 mg, 0.58 mmol). The reaction was stirred at room temperature, then partitioned S between DCM/brine. The organic layer was concentrated under reduced pressure. Flash chromatography on silica gel (0% - 30% EtOAc/hexanes over 10 column volumes then 30% - 100% EtOAc/hexanes over 5 column volumes) gave incomplete separation of starting material and product. Repurification by reverse phase chromatography (0% - 60% MeCN/H 2 0, both containing 0.1 % TFA) provided the title compound as a white solid. LC-MS (ESI): m/z = 505.3 [M+1] .
1 H NMR (500 MHz, CD 3 OD): a 8.00 (d, SJ= 8.4 Hz, 2H), 7.52 (d, J = 8.5 Hz, 2H1), 7.47 (d, J = 2.3, 1H), 7.01 (dd, J= 8.6, 2.4 Hz, 1H), 6.67 (d, J -49 - WO 2007/111864 PCT/US2007/006806 8.4 Hz, 1H), 3.89 (s, 3H), 2.83 (d, J = 13.3 Hz, 2H), 2.30 (m, 1H), 1.98 - 1.89 (overlapping t, d, 4 H), 1.41 (q, 2H). Step B: Methyl 4-41 -[2-(4-tert-butvlphenvl)- 1-benzofuran-5-vll-4-(trifluoromethyl)cyclohexyl] benzoate 5 To a solution of the title compound from the previous step (36mg, 0.07 mmol), copper iodide (1 mg, 0.005 mmol) and bis(triphenylphosphine)palladium(II) acetate (1 mg, 0.001 mmol) in 0.50 mL of DMF were added 4-tert-butylphenylacetylene (0.013 mL, 0.07 mmol), and piperidine (0.007 mL, 0.07 mmol). The reaction mixture was heated at 85 °C overnight, then partitioned into EtOAc/brine. The aqueous layer was washed twice with EtOAc. The combined organic phase was concentrated under 0 reduced pressure to provide the crude product which was used without further purification. LC-MS (ESI): m/z= 535.4 [M+1] *. Step C: 4-rl-[2-(4-tert-Butvlphenyl)-1 -benzofuran-5-Yll-4-(trifluoromethyl)cvclohexvllbenzoic acid To the title compound from the previous step (0.07 mmol) in 1 mL of dioxane was added 5 a solution of LiOH (8 mg, 0.33 mmol) in 0.5 mL of water. The reaction was stirred at 45 *C for 2 h. The reaction mixture was partitioned between aqueous pH 7 buffer and EtOAc. The organic phase was collected and the aqueous layer was washed 2 times with EtOAc. The combined organic phase was concentrated under reduced pressure to provide the title compound which was used without further purification. LC-MS (ESI): m/z = 521.4 [M+1] . 0 Step D: 3-({4-fl-f2-(4-tert-Butylphenyl)-I -benzofuran-5-vil-4-(trifluoromethyl) cyclohexyllbenzoyl. amino)propanoic acid To a solution of the title compound from the previous step, j-alanine tert-butyl ester hydrochloride (25 mg, 0.14 mmol), HOBt (21 mg, 0.14 mmol) and EDC (27 mg, 0.14 mmol) in 1 mL of 5 DMF was added DIEA (0.037 mL, 0.21 mmol). The reaction mixture was heated to 45 'C for lh, allowed to stand at room temperature for 16 h, then partitioned between EtOAc/water. The organic layer was collected and the aqueous layer was washed twice with EtOAc. The combined organic phase was concentrated under reduced pressure. LC-MS (ESI): m/z= 648.4 [M+1] +. The residue was dissolved in 0.70 mL of DCM with 0.015 mL of water and 0.30 mL of trifluoroacetic acid. The reaction was stirred at S room temperature for 1 h. The solvent was removed and the product was purified by reverse phase chromatography (70% - 100% MeCN/H 2 0, both containing 0.1% TFA). Lyophilization afforded the title compound as a white solid. LC-MS (ESI): m/z = 592.3 [M+1]
+
. 'H NMR (500 MHz, CD 3 OD): 5 7.80 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.5 Hz, 2H), 7.56 (d, J = 8.5, 2H), 7.48 (overlapping d, d, 3H), 7.33 (d, J= 8.7 Hz, 1H), 7.14 (dd, J= 8.7 Hz, 2.1 Hz, 1iH), 7.03 (s, 1H), 3.62 (t, 2H), 2.97 (d, J= 13.9 Hz, 2H), 2.62 5 (t, 2H), 2.33 (m, 1H), 2.09 (t, 2H), 1.95 (br d, 2H), 1.50 (q, 2H), 1.34 (s, 9H). -50- WO 2007/111864 PCT/US2007/006806 EXAMPLE 9 Cl CI
F
3 C -~ 0 0 O N -0OH H Step A: Methyl 4-[1l-( 3 -chloro- 4 -hydroxy-5-iodophenyl)-4-(trifluoromethyl)cyclohexyl1benzoat The title compound of Example 8, Step A (0.08 mmol, 40 mg) was taken up in SO 2 C1 2 5 (0.5 mL) and the resulting solution was heated at 50 OC for 45 min. The reaction mixture was concentrated under reduced pressure and the residue was taken up in DCM and washed with brine. The organic phase was dried with Na 2
SO
4 and concentrated in vacuo to provide the title compound as a foam which was used without further purification. 0 Step B: Methyl 4-l[1-(7-chloro-2-propvl-1-benzofuran-5-yl)-4-(trifluoromethyl)cyclo-hexyllbenzoate To the title compound of the previous step (0.08 mmol) in DMF (0.2 mL) was added 1 penyne (0.1 mmol, 0.010 mL), Cul (0.02 mmol, 4 mg), PdCI 2 (Ph 3
P)
2 (0.01 mmol, 7 mg) and DIEA (0.2 mmol, 0.034 mL). The reaction mixture was heated with stirring at 75 'C for 2 h, then at 60 *C for 16 h. The reaction mixture was partitioned between DCM/brine. The organic layer was concentrated in vacuo 5 and the product was isolated by preparative TLC on silica eluting with 15% EtOAc/hexanes to provide the title compound as a yellow solid. Step C: N-4- l-(7-Chloro-2-propyl-1-benzofuran-5-yl)-4-(trifluoromethyl)cyclohexyl] benzoyl}-3 alanine. ) To the title compound from the previous step in 2 mL of dioxane was added a solution of LiOH (1 mmol, 24 mg) in 1 mL of H 2 0. The resulting solution was stirred at 40 °C for 1.5 h, then partitioned between DCM/1N HCI (aq). The organic phase was dried over Na 2
SO
4 and concentrated in vacuo. The residue was taken up in DMF (1 mL) and 3-alanine ethyl ester hydrochloride (0.1 mmol, 16 mg), EDC (0.1 mmol, 19 mg) and HOBt (0.1 mmol, 16 mg) were added, followed by DIEA (0.15 mmol, 0.026 mL). The reaction mixture was heated at 40 'C for 2 h, then partitioned between DCM/brine. The organic phase was concentrated in vacuo and the resulting residue was taken up in 4 mL of dioxane. A solution of LiOH (1 mmol, 24 mg) in 1 mL of H 2 0 was added and the resulting solution was stirred at 40 'C for 1.5 h. The reaction was acidified by addition of TFA (0.10 mL), then purified by reverse phase HPLC (60% - 100% MeCNIH20, both containing 0.1 % TFA). Lyophilization provided the title compound as a white solid. LC-MS (ESI): m/z= 536.1 [M+1] . 'H NMR (500 MHz, d 6 -DMSO): 6 7.79 -51 - WO 2007/111864 PCT/US2007/006806 (d, 3=8.7 Hz, 2H); 7.53 (d, J=8.7 Hz, 2H); 7.30 (d, J=1.6 Hz, 111); 7.04 (d, J=1.6 Hz, 1H); 6.43 (s, 1H); 3.62 (t, J=7.0 Hz, 2H); 2.92 (d, J=13.3 Hz, 2H); 2.73 t, J=7.3 Hz, 2H); 2.63 (t, J=7.0 Hz, 2H11); 2.31 (m, 1H); 2.03 (td, J=13.6 Hz, 3 Hz, 2H11); 1.93 (m, 2H11); 1.75 (min, 2H); 1.46 (min, 2H); 0.98 (t, J=14.5 Hz, 3H). 5 EXAMPLES 10 and 11 Br Br o o Br 0 0 O N' OH O N' OH H H Step A: Methyl 4 -[2-(3-bromo-4-hvdroxyphenyl)bicyclof2.2.1lhept-2-.yllbenzoate and Methyl 4-[2-(3,5 dibromo-4-hydroxyphenyl)bicycloF[2.2.1 lhept-2-vyllbenzoate Intermediate 7, Isomer B (1 mmol, 322 mg) and N-bromosuccinimide (1.3 mmol, 231 0 mg) were combined in DCM (5 mL) and the reaction mixture was allowed to stand at room temperature for 16 h. The reaction mixture was taken up in DCM and washed with saturated NaHCO 3 (aq), then brine. The resultant mixture of starting material, monobromo- and bisbromo products were concentrated in vacuo and taken directly to the next step. Monobromide LC-MS (ESI): m/z = 403.0 [M+3] , 401.0 [M+1] +; Bisbromide LC-MS (ESI): m/z = 481.0 [M+3] , 482.9 [M+5] , 479.0 [M+1] . Step B: Methyl 4- 2
-[
3 -bromo-4-(Ceyclohexylmethoxy)phenyllbicyclof2.2.1 lhept-2-yl benzoate and Methyl 4-f 2 -[3,5-dibromo-4-(cyclohexylmethoxy)phenyl]bicyclo[2.2.11 hept-2-yl}benzoate To the product from the previous step in DMF (5 mL) was added bromomethyleyclohexane (2 mmol, 0.28 mL) and Cs 2
CO
3 (2 mmol, 650 mg). The reaction mixture was ) heated with stirring at 50 °C for 16 h, then partitioned between DCM/brine. The organic phase was dried over Na 2
SO
4 and concentrated. The residue was taken up in minimum DCM and passed through a silica plug eluting with 15 % EtOAc/hexanes. The filtrate containing the des-bromo, mono-bromo and bis bromo ethers was concentrated to a beige solid and used without further purification. Step C: N-( 4 -{2-[ 3 -bromo-4-.(cyclohexylmethoxv)phenyllbicyclo[2.2.1 hept-2-yl benzoyl)-13-alanine and N-(4-f2-[35-dibromo-4-( loexlmethox)henvllbicvclo [2.2.1 hept-2-yl }benzovyl)-13-alanine To the mixture from the previous step in 2 mL of dioxane was added a solution of LiOH (I mmol, 24 mg) in 0.5 mL of H20. The resulting solution was stirred at 40 'C for 3 h, then partitioned between DCM/1N HCI (aq). The organic phase was dried over Na 2
SO
4 and concentrated in vacuo. The residue was taken up in DMF (1 mL) and P3-alanine ethyl ester hydrochloride (0.2 mmol, 31 mg), EDC -52 - WO 2007/111864 PCT/US2007/006806 (0.2 mmol, 38 mg) and HOBt (0.2 mmol, 31 mg) were added, followed by DIEA (0.3 mmol, 0.052 mL). The reaction mixture was allowed to stand at room temperature for 16 h, then partitioned between DCM/brine. The organic phase was concentrated in vacuo and the resulting residue was taken up in 2 mL of dioxane. A solution of LiOH (1 mmol, 24 mg) in 1 mL of H20 was added and the resulting solution 5 was stirred at 40 *C for 2 h. The reaction was acidified by addition of TFA (0.10 mL), and purified by reverse phase HPLC (60% to 100% MeCN/H 2 0, both containing 0.1 % TFA) to provide monobromide title compound Example 10 and bisbromide title compound Example 11. Example 10: LCMS (ESI): m/z = 556.2 [M+3] ; 554.2 [M+1] . 1H NMR (500 MHz, d 6 -DMSO): 8 12.18 (br s, 1Ff); 8.39 (t, J=5.6 Hz, 1H); 7.66 (d, J=8.5 Hz, 2H); 7.46 (d, J=2.5 Hz); 7.38 (d, J=8.2 Hz); 7.30 (dd, 0 J=8.7 Hz, J=2.3 Hz, 1H); 6.90 (d, J=8.7 Hz, 1H); 3.74 (d, J=6.4 Hz, 2H); 2.46 (t, J=7.0 Hz, 2H); 2.34 (inm, IH); 2.25 (m, 2H); 1.77 (min, 2H11); 1.57-1.73 (overlapping m, 4H); 1.36-1.51 (overlapping m, 3H); 1.32 (d, J=9.2 Hz, 1H); 0.06-1.28 (overlapping m, 7H); 3H obscured by solvent from 3.3-3.6 ppm. Example I11: LCMS (ESI): m/z = 634.0 [M+3] +; 636.1 [M+5] +; 632.1 [M+1] +. 'H NMR (500 MIHz, d6 DMSO): 8 12.20 (br s, 1H); 8.43 (t, J=5.4 Hz, 1H); 7.69 (d, J=8.2 Hz, 2H); 7.60 (s, 2H); 7.45 (d, J=8.2 5 Hz, 2H); 3.66 (d, J=5.9 Hz, 2H); 2.47 (t, J=7.1 Hz, 2H); 2.35 (min, 1H); 2.27 (m, 2H)1.58-1.86 (overlapping m, 6H); 1.37-1.52 (overlapping m, 3H); 1.33 (d, J=9.4Hz, 1H); 1.00-1.29 (overlapping m, 7H); 3H obscured by solvent from 3.24-3.50 ppm. EXAMPLE 12 CN 0 I 0 N >kOH H Step A: Methy 4
-
2
-[
3 -cyano-4-(cycloexvlmethoxy)phenvlbieclor2.2.1 hept-2-yl} benzoate The product mixture from Example 10, Step B (0.1 mmol, 53 mg), Zn(CN) 2 (0.15 mmol, 18 mg), Pd 2 dba 3 (0.01 mmol, 9 mg) and bis(diphenylphosphino)ferrocene (0.024 mmol, 13 mg) were heated in DMF (0.4 mL) containing H 2 0 (0.008 mL) at 110 °C for 14 h. The reaction mixture was partitioned between DCM/brine and the organic phase was passed through a 0.45 micron filter and concentrated in vacuo. The crude reaction mixture was taken directly to the next step. Step B: N-(4- { 2
-
3 -cyano-4-(cyclohexvlmethoxvy)phenyl]bicyclor2.2.1 lhept-2-vl} benzoyl)-3-alanine To the product from the previous step in 1 mL of dioxane was added a solution of LiOH (1 mmol, 24 mg) in 0.5 mL of H20. The resulting solution was stirred at 40 *C for 3 h, then partitioned - 53 - WO 2007/111864 PCT/US2007/006806 between DCM/1N HCI (aq). The organic phase was dried over Na 2
SO
4 and concentrated in vacuo. The residue was taken up in DMF (1 mL) and | 3 -alanine ethyl ester hydrochloride (0.2 mmol, 31 mg), EDC (0.2 mmol, 38 mg) and HOBt (0.2 mmol, 31 mg) were added, followed by DIEA (0.3 mmol, 0.05 mL). The reaction mixture was allowed to stand at ambient temperature for 16 h, then partitioned between 5 DCM/brine. The organic phase was concentrated in vacuo and the resulting residue was taken up in 2 mL of dioxane. A solution of LiOH (1 mmol, 24 mg) in I mL of H 2 0 was added and the resulting solution was stirred at 40 °C for 2 h. The reaction was acidified by addition of TFA (0.10 mL), and the mononitrile product was isolated by reverse phase HPLC (40 - 100% MeCN/H 2 0, both containing 0.1 % TFA). Lyophilization provided the title compound as a white solid. LCMS (ESI): m/z = 501.3 [M+1] +. 'H 0 NIMR (500 MHz, d 6 -DMSO): 8 12.18 (br s, 1H); 8.39 (t, J=5.5 Hz, 1H); 7.70 (d, J=2.5 Hz, 1H); 7.66 (d, J=8.5 Hz, 2H); 7.56 (dd, J=8.9 Hz, J=2.5 Hz, 1H); 7.40 (d, J=8.4 Hz, 2H); 7.03 (d, J=9Hz, 1H); 3.83 (d, J=6.2 Hz, 2H); 2.45 (t, J=7.1 Hz, 2H); 2.34 (s, 1H); 2.26 (s, 2H); 1.57-1.78 (overlapping m, SH); 1.46 1.55 (overlapping m, 4H); 1.31 (mn, 1H); 0.95-1.28 (overlapping m, 71H); 3.2-3.5 3H obscured by solvent. 5 EXAMPLE 13 0 o
F
3 C 0 0 o N OH H Step A: Methyl 4-l 1-(2-oxo-3.
4 -dipropvl-2H-chromen-7-vl)A-4-(trifluoromethyl)cyclohexvl]benzoate To a solution of the title compound of Example 8, Step A (16mg, 0.03 mmol), tetrabutylammonium chloride (8.3 mg, 0.03 mmol) and palladium acetate (1mg, 0.004 mmol) in 0.5 mL ) of DMF was added pyridine (0.005 mL, 0.06 mmol) and 4-octyne (0.022 mL, 0.15 mmol). The reaction was flushed with CO, then heated under an atmosphere of CO (balloon) overnight at 115 'C. The reaction was partitioned between EtOAc/water and the aqueous layer was washed twice with EtOAc. The combined organic phase was concentrated under reduced pressure. The product was purified by flash chromatography on silica gel eluting with a gradient of 0% - 20% EtOAc/hexanes over 10 column volumes, then 20% - 100% EtOAc/hexanes over 10 column volumes, to afford the title compound as a white solid. LC-MS (ESI): nm/z =515.5 [M+1] . -54 - WO 2007/111864 PCT/US2007/006806 Step B: 4-[ I -(2-Oxo-3,4-dipropyl-2H-chromen-7-vyl)-4-(trifluoromethyl)cyclohexvl]benzoic acid To the title compound from the previous step (6 mg, 0.01 mmol) in 1 mL of dioxane was added a solution of LiOH (5 mg, 0.21 mmol) in 0.5 mL of water. The reaction mixture was stirred at room temperature overnight and taken up in aqueous pH 7 buffer and EtOAc. The organic layer was 5 collected and the aqueous layer was washed twice with EtOAc. The combined organic phase was concentrated under reduced pressure to provide the title compound. LC-MS (ESI): m/z =501.4 [M+I] +. Step C: 3-({4-f rl-(2-Oxo-3.4-dipropyl-2H-chromen-7-vl)-4-(trifluoromethyl)cgyclohexvll]benzoylI amino)propanoic acid 0 To a solution of the title compound from the previous step (0.01 mmol), 3-alanine tert butyl ester hydrochloride (4 mg, 0.02 mmol), HOBt (3 rmg, 0.02 mmol) and EDC (4 mg, 0.02mmol) in 0.8 mL DMF was added DIEA (0.005 mL, 0.03 mmol). The reaction was heated at 45 0 C for lh, then partitioned between EtOAc/water. The organic layer was collected and the aqueous layer was washed 2 times with EtOAc. The combined organic phase was concentrated under reduced pressure. LC-MS (ESI): 5 m/z = 628.6 [M+1] +. The residue was dissolved in 0.70 mL DCM with 0.015 mL of water and 0.30 mL trifluoroacetic acid. The reaction was stirred at room temperature for 45 min. The solvent was removed and the product was purified by reverse phase chromatography (30% - 100% MeCN/H 2 0, both containing 0.1 % TFA). Lyophilization afforded the title compound as a white solid. LC-MS (ESI): m/z = 572.5 0 [M+1] . 'H NMR (500 MHz, CD30D): 8 7.86 (d, J = 8.5 Hz, 2H), 7.56 (overlapping d, m, 3H), 7.22 (m, 2H), 3.63 (t, 2H), 2.89 (d, J = 13 Hz, 2H), 2.68 -2.62 (overlapping m, 4H), 2.55 (m, 2H), 2.38 (m, 1H), 2.11 (t, 2H), 1.96 (br d, 2H), 1.55 - 1.46 (overlapping m, 4H), 1.40 (m, 2H), 1.00 - 0.94 (overlapping m, 611). 5 EXAMPLE 14
F
3 C 0 0 0 O N KOH H -55 - WO 2007/111864 PCT/US2007/006806 Step A: Methyl 4-fl -f 2-F( E)-prop- 1-en-1 -vll-3.4-dihyvdro-2H-chromen-6-yl -4-(trifluoromethyl) cyclohexyllbenzoate To the title compound of Example 8, Step A (27 mg, 0.05 mmol) in 0.5 mL of DMF was added palladium acetate (1.2 mg, 0.005 mmol), lithium chloride (4.2 mg, 0.1 mmol), DIEA (0.070 mL, 5 0.4 mmol), and 1,4-hexadiene (0.046 mL, 0.4 mmol). The reaction was stirred at 95 °C for 16 h, then partitioned between EtOAc/water. The organic layer was collected and the aqueous layer was washed twice with EtOAc. The combined organic layers were concentrated under reduced pressure. The product was purified by flash chromatography on silica gel eluting with a gradient of 0% - 30% EtOAc/hexanes over 10 column volumes, then 30% - 100% EtOAc/hexanes over 5 column volumes, to afford the title 0 compound as a yellow oil. LC-MS (ESI): m/z = 459.2 [M+1]'. Step B: Methyl 4-l-(2-opropyl-3, 4 -dihbydro-2H-chromen-6-yl)-4-(trifluoromethyl)cyclohexv2lbenzoate To the title compound from the previous step (7.5 mg, 0.016 mmol) in 1 mL EtOAc was added catalytic 20% palladium hydroxide on carbon. The reaction was stirred for 5.5 h at room 5 temperature under H 2 (balloon). The solution was filtered through celite and the filtrate was concentrated under reduced pressure to provide the title compound which was used without further purification. LC MS (ESI): m/z = 461.2 [M+1] +. Step C: 4-l-( 2 -Pronpyvl-34-dihydro-2H-chromen-6-.vl)-4-(trifluoromethyl)cyclohexvllbenzoic acid 0 To the title compound from the previous step (0.016 mmol) in 1 mL of dioxane was added a solution of LiOH (10 mg, 0.4 mmol) in 0.5 mL of water. The reaction was stirred at room temperature overnight. The reaction mixture was partitioned between aqueous pH 7 buffer and EtOAc. The organic layer was collected and the aqueous layer was washed 2 times with EtOAc. The combined organic layers were concentrated under reduced pressure. LC-MS (ESI, neg. ion): m/z = 445.3 [M-I]-. 5 Step D: 3-(f4-r1-( 2 -Propvl- 3
,
4 -dihydro-2H-chromen-6-yl)-4-(trifluoromethyl)cycloexl]benzy)y} amino)propanoic acid To a solution of the title compound from the previous step (0.016 mmol), P3-alanine tert butyl ester hydrochloride (6 mg, 0.03 mmol), HOBt (5 mg, 0.03 mmol) and EDC (6 mg, 0.03 mmol) in ) 0.5 mL DMF was added DIEA (0.008 mL, 0.05 mmol). The reaction was heated at 40 *C for lh, then partitioned between EtOAc/water. The organic layer was collected and the aqueous layer was washed 2 times with EtOAc. The combined organic layers were concentrated under reduced pressure. LC-MS (ESI): m/z = 574.4 [M+1]. The residue was dissolved in 0.70 mL of DCM containing 0.015 mL of water and 0.30 mL of trifluoroacetic acid. The reaction was stirred at room temperature for 1 h. The solvent S was removed and the product was purified by reverse phase chromatography (30% - 100% MeCN/H 2 0, both containing 0.1 % TFA). Lyophilization afforded the title compound as a white solid. LC-MS (ESI): m/z= 518.3 [M+1] . 'H NMR (500 MHz, CD 3 OD): 5 7.77 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.5 Hz, 2H), - 56 - WO 2007/111864 PCT/US2007/006806 6.87 (overlapping d, d, 2H), 6.55 (d, J = 8.7 Hz, 1H), 3.89 (m, IH), 3.62 (t, 2H), 2.84 (br d, 2H), 2.73 2.62 (overlapping m, d), 2.27 (min, 1H), 1.98 - 1.88 (overlapping m), 1.67 - 1.39 (overlapping min), 0.95 (t, 2H). 5 EXAMPLE 15 MeN / CF 3
F
3 C N O NH C O g H Step A: Dimethyl 4,4'- r 4 -(trifluoromethyl)cyclohexane-1 ,1-diylldibenzoate The title compound was prepared from the bis-triflate product from Intermediate 5, Method 2, Step A using conditions analogous to those described in Intermediate 5, Method 2, Step B. 0 LC-MS (ESI): mn/z = 421.3 [M+1] +. 'H NMR (500 MHz, CD30D): 8 8.02 (d, J = 8.5 Hz, 2H), 7.89 (d, J 8.7 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.7 Hz, 2H), 3.90 (s, 3H), 3.86 (s, 3H), 2.96 (br d, J= 13.2 Hz, 2H), 2.35 (min, 1H), 2.05 (t, 2H), 1.96 (brd, 2H), 1.48 (q, 2H). Step B: 4- 1-f 4 -(Methoxvearbonvyl)phenyll-4-(trifluoromethyl)cyclohexyllbenzoic acid 5 To the title compound from the previous step (630 mg, 1.5 mmol) in 9.5 mL of 1,4 dioxane and 5 mL of water was added portionwise LiOH (49 mg, 2 mmol). The reaction mixture was heated at 40 oC for 2 h, acidified with 2N HCI (aq) and extracted twice with EtOAc. The organic phase was concentrated in vacuo and the resultant residue was separated by preparative thin layer chromatography on silica gel (15% MeOH in dichloromethane) to provide the title compound. LC-MS (ESI, neg. ion): m/z = 405.2 [M-l] -. Step C: Methyl 4-1- {4- 1-methyl-5-(trifluoromethvl)-lH-benzimidazol-2vl]phenvl}-4 (trifluoromethvl)cyclohexyllbenzoate To the title compound from the previous step (40 mg, 0.1 mmol) and 0.5 mL of POCi 3 S was added 1-N-methyl- 4 -trifluoromethyl-1,2-phenylenediamine (23 mg, 0.12 mmol). The resulting mixture was heated at 80 oC for 2.5 h. Another 30 mg (0.16 mmol) of the phenylenediamine was introduced and the reaction mixture was heated at 80 oC for another l h. The reaction was concentrated in vacuo and the residue was purified on reverse phase HPLC (10% to 100% MeCN/H 2 0, each containing 0.05% (v/v) of TFA) to provide the title compound as a mixture of isomers. LC-MS (ESI): m/z = 561.3 [M+I]+. -57- WO 2007/111864 PCT/US2007/006806 Step D: N-{4-41- {4-F -Methvl-5-(trifluoromethyl-]H-benzimidazol-2-vlphenyl-4(trifluoromethyl) cyclohexyllbenzoyl l-13-alanine To the title compound from the previous step (30 mg, 0.054 mmol) in 0.5 mL of 1,4 dioxane and 0.25 mL of water was added LiOH (17 mg, 0.7 mmol). The resultant mixture was stirred at 5 ambient temperature for 16 h, acidified with IN HCI, and extracted with EtOAc. The organic phase was concentrated to afford the acid. LC-MS (ESI): m/z = 547.3 [M+I] +. The crude acid was treated with EDC (21 mg, 0.1 mmol), HOBt (17 mg, 0.12 mmol), 3 alanine tert-butyl ester hydrochloride (20 mg, 0.11 mmol) and DIEA (0.033 mL, 0.2 mmol) in 0.5 mL DMF at ambient temperature for 2.5 h. The reaction mixture was partitioned between water and EtOAc. 0 The organic phase was washed with water, concentrated and the residue was taken up in a mixture of 0.25 mL of TFA and 0.5 mL of dichloromethane. After 4 h, the solvent was removed and the residue was purified by reverse phase HPLC (30% to 100% MeCN/H 2 0, each containing 0.05% (v/v) of TFA) to give the title compound as a mixture of two isomers. LC-MS (ESI): m/z = 618.2 [M+I]+. 5 EXAMPLE 16
-
OCF3 N
F
3 C H N OH 0 Step A: Methyl 4-[1-( 4 -hydroxy- 3 -nitrophenyl)-4-(trifluoromethyl)cyclohexyllbenzoate To Intermediate 5, Isomer B (228 mg, 0.6 mmol) in a mixture of 14 mL of acetonitrile and 5 mL ofdichloromethane was added ceric ammonium nitrate (509 mg, 0.93 mmol). After 20 min the ) reaction mixture was partitioned between hexanes-EtOAc-DCM and aq. sodium bisulfite. The organic phase was purified by flash chromatography on silica gel eluting with 20% EtOAc/hexanes to provide the title compound. 1H NMR (500 MHz, CD 2 C1 2 ): 8 (ppm) 10.41 (s, 1H), 8.03 (d, J= 8.5 Hz, 2H), 7.98 (d, J = 2.3 Hz, 1H), 7.46 (d, J= 8.5 Hz, 2H), 7.37 (dd, J= 8.9, 2.5 Hz, 1H), 7.03 (d, J= 8.9 Hz, 1H), 3.90 (s, 3H11), 2.86 (d, J= 14.2 Hz, 2H), 2.23 (min, 1H). Step B: Methyl 4-[1-( 3 -amino- 4 -hydroxyphenyl)-4-(trifluoromethyl)evelohexyllbenzoate The title compound from the previous step (124 mg, 0.29 mmol) in 1.4 mL of DMF and 0.14 mL of water was treated with tin(I) chloride dihydrate (335 mg, 1.5 mmol). The reaction was heated at 50 oC until reaction was complete as indicated by TLC. The reaction mixture was diluted with ca. 50 mL of 1:1 (v/v) hexanes:EtOAc and 10 mL ofaq. sodium bicarbonate. The resulting slurry was filtered and the filtrate was partitioned between EtOAc/brine. The organic phase was purified by flash - 58 - WO 2007/111864 PCT/US2007/006806 chromatography on silica gel eluting with a gradient of 33% to 50% EtOAc/hexanes to provide the title compound. 1H NMR (500 IMHz, acetone-d6): 8 (ppm) 7.98 (d, J= 8.2 Hz, 2H), 7.58 (d, J= 8.6 Hz, 2H), 6.60 (min, 2H), 6.39(dd, J= 8.2, 2.3Hz, 1H), 3.88 (s, 3H). 5 Step C: Methyl 4-fl-[2-(4-fluorophenyl)-1, 3 -benzoxazol-5-yll-4-(trifluoromethyl)cyclohexyllbenzoate A solution of the title compound from the previous step (19 mg, 0.05 mmol), 4 trifluoromethoxybenzoyl chloride (0.016 mL, 0.1 mmol) and triethylamine (0.023 mL, 0.17 mmol) in 0.5 mL of dichloromethane was stirred for 15 min. Solvent was removed in vacuo and the residue was taken up in 0.5 mL of MeOH and heated at 40 oC for lh. Solvent was removed in vacuo and to the resultant 0 residue were added p-toluenesulfonic acid hydrate (37 mg, 0.2 mmol) and toluene (2 mL). The reaction mixture was heated at 120 C for 50 min, and was partitioned between EtOAc and aq. sodium bicarbonate. The organic layer was concentrated to give the title compound which was used without further purification. LC-MS (ESI): m/z = 564.3 [M+1] . 5 Step D: N-f4-[ l-2-(4-Fluorophenvyl)-1, 3 -benzoxazol-5-yll-4-(trifluoromethyl)cyclohexyll]benzovll-13 alanine The title compound from the previous step was treated with 0.5 mL of 1 N NaOH (aq) in 1 mL of 1,4-dioxane at 50 oC for lh 15 min. The mixture was acidified by addition of dilute HCI and extracted with EtOAc. The organic phase was concentrated and the resultant residue was taken up in 0 DMF (1 mL) and treated with EDC (40 mg, 0.2 mmol), HOBt (40 mg, 0.2 mmol), 13-alanine tert-butyl ester hydrochloride (40 mg, 0.2 mmol) and DIEA (0.06 mL, 0.4 mmol) at 50 'C for 25 min. The reaction mixture was partitioned between water and EtOAc. The organic phase was concentrated and the residue was taken up in a mixture of 0.5 mL of TFA and 1 mL of dichloromethane. After 2 h the solvent was removed and the residue was purified by reverse phase HPLC (45% to 100% MeCN/H 2 0, each 5 containing 0.05% (v/v) of TFA) to give the title compound. LC-MS (ESI): m/z =621.3 [M+1] +. 'H NMR (500 MHz, acetone-d6): 8 (ppm) 8.34 (d, J= 8.9 Hz, 2H), 7.91 (d, J= 8.5 Hz, 2H), 7.82 (t, J= 5.4 Hz, 1H), 7.69 (d, J= 1.8 Hz, 1H), 7.64 (d, J= 8.5 Hz, 2H11), 7.56 (min, 3H), 7.34 (dd, J= 8.7, 2.0 Hz, 1H), 3.64 (min, 2H11), 3.08 (d, J= 13.3 Hz, 2H), 2.65 (t, J= 6.9 Hz, 2H11), 2.46 (min, 1H), 2.16 (m, 2H), 1.99 (inm, 2H), 1.52 (m, 2H). D EXAMPLE 17 - 59 "- OH N O H - 59 - WO 2007/111864 PCT/US2007/006806 Step A: Methyl 4-Fl -{4-f(4-fluorophenvl)ethvnvll-3-nitrophenyl}-4-(trifluoromethvl)cyclohexyll benzoate To the title compound of Example 16, Step A (24 mg, 0.057 mmol) in DCM (1 mL) was added 0.03 mL each ofpyridine and trifluoromethanesulfonic anhydride. After 1 h, aqueous workup 5 provided the crude triflate. A portion of the crude triflate (22 mg) was taken up in THF (0.6 mL), then Pd(OAc) 2 (2.7 mg, 0.01 mmol), PPh 3 (7.6 mg, 0.03 mmol), 1-ethynyl-4-fluorobenzene (18 mg, 0.15 mmol) and triethylamine (0.3 mL) were added. The resultant mixture was heated to 70 oC for 2.5 h. The reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC on silica gel (12% EtOAc/hexanes) to provide the title compound. 1H NMR (500 MHz, CDCI 3 ): 8 (ppm) 8.07 (d, J= 0 8.5 Hz, 2H), 7.96 (d, J= 2.1 Hz, 1H), 7.33 (dd, J= 8.5, 2.1 Hz, 1H), 7.07 (in, 2H), 3.93 (s, 3H), 2.88 (d, J = 12.1 Hz, 2H), 2.21 (min, 1H), 1.53 (min, 2H). Step B: Methyl 4-[ 1-f 3-amino-4-[(4-fluorophenyl)ethynvyl]phenyl}-4-(trifluoromethyl)cyclohexylI benzoate 5 To the title compound from the previous step (17 mg, 0.034 mmol) in 0.3 mL of DMF and 0.03 mL of water was added tin(I) chloride dihydrate (34 mg, 0.15 mmol). The reaction was heated at 40 oC for lh. The reaction mixture was partitioned between a 1:1 (v/v) mixture of hexane/EtOAc and aq. sodium bicarbonate. The organic layer was filtered and concentrated in vacuo. The resulting residue was purified by preparative TLC on silica gel (33% EtOAc/hexanes) to give the title compound. 1H NMR 0 (500 MHz, DMF-d 7 ): 8 (ppm) 7.98 (d,J= 8.5 Hz, 2H), 7.63 (mn, 4H1), 7.21 (min, 2H), 7.15 (d,J= 8.2 Hz, 11), 6.73 (d, J= 1.8 Hz, 1H), 6.54 (dd, J= 8.2, 1.8 Hz, 1H), 3.88 (s, 3H), 3.67 (min, 2H), 1.38 (in, 2H). Step C: Methyl 4-f l-[2-(4-fluorophenvl)- IH-indol-6-vll-4-(trifluoromethyl)cyclohexyllbenzoate The title compound from the previous step (10 mg, 0.02 mmol) and PdCI 2 (1.1 mg, 0.006 5 mmol) were heated in 1 mL of acetonitrile for 1 h. Removal of solvent gave the crude product which was carried over to the next step without further purification. 'H NMR (500 MHz, CDCI 3 ): 8 (ppm) 8.56 (s, 1H), 8.03 (d, J= 8.5 Hz, 2H), 7.66 (min, 2H), 7.54 (d,J= 8.7 Hz, 2H11), 7.48 (d,J= 8.4 Hz, 1H), 7.27 (s, 1H), 7.17 (min, 2H), 7.00 (dd, J= 8.5, 1.6 Hz, 1H1), 6.71 (s, IH), 3.91 (s, 3H), 2.96 (d, J= 13.3 Hz, 2H), 2.27 (min, 1IH), 1.55 (m, 2H). 0 Step D: N- {4-[1 -[2-(4-Fluorophenvl)- IH-indol- 6 -vll-4-(trifluoromethyl)cyclohexvyllbenzoyvi }-3-alanine The title compound from the previous step was saponified in a mixture of I mL of 1,4 dioxane and 0.5 mL of I N NaOH at 50 0C for 3.5 h. The reaction mixture was acidified by addition of dilute HCI and extracted with EtOAc. The organic phase was concentrated and the resultant residue was 5 taken up in DMF (1 mL) and treated with EDC (40 mng, 0.2 mmol), HOBt (40 mg, 0.2 mmol), 3-alanine tert-butyl ester hydrochloride (40 mg, 0.2 mmol) and DIEA (0.6 mL, 0.4 mmol) at 50 C for 25 min. The reaction mixture was partitioned between water and EtOAc. The organic phase was concentrated and the - 60 - WO 2007/111864 PCT/US2007/006806 residue was taken up in a mixture of 0.5 mL of TFA and I mL of dichloromethane. After 2h the solvent was removed and the residue was purified on reverse phase HIPLC (45% to 100% MeCN/H 2 0, each containing 0.05% (v/v) of TFA) to provide the title compound. 'H NMR (500 MHz, acetone-d 6 ): 8 (ppm) 10.54 (s, 1H), 7.89 (d, J= 8.5 Hz, 2H), 7.85 (m, 3H), 7.59 (d, J= 8.5 Hz, 2H), 7.42 (d, J= 8.5 Hz, 1H), 5 7.20 (m, 2H), 7.14 (s, 1H), 7.03 (dd, J= 8.5, 1.6 Hz, 1H), 6.76 (d, J= 1.8 Hz, lI), 3.65 (m, 2H), 2.96 (d, J= 13.7 Hz, 2H), 2.66 (t, J= 6.9 Hz, 2H), 2.44 (m, 1H), 2.16 (m, 2H), 1.95 (m, 2H), 1.50 (m, 2H). EXAMPLE 18, ISOMERS A and B
CF
3 \ ,N
F
3 C " H /N -- ,OH 0 0 0 Step A: 4-(Trifluoromethyl)-1-[ 7 -(trifluoromethyl)quinolin-3-v1]cyclohexanol To a cold (-78 oC) anhydrous THF solution of 2-methoxy-6-bromoquinoline (300 mg, 1.09 mmol) was added BuLi (0.46 mL of a 2.5 M solution in hexanes, 1.14 mmol). The mixture was stirred at -78 oC under a nitrogen atmosphere for 15 min, then 4 -(trifluoromethyl)cyclohexanone (180 mg, 1.14 mmol) was slowly added. After addition, the dry ice/acetone bath was allowed to warm to room 5 temperature. The reaction mixture was quenched with saturated NH 4 CI solution, then extracted with EtOAc/hexanes. The organic layer was evaporated in vacuo. The crude residue was purified by flash chromatography on silica gel using gradient elution (0% to 20% EtOAc/hexanes, 60 mL; 20% to 35% EtOAc/hexanes, 100 mL; 35% to 75% EtOAc/hexanes, 246 mL) to give the title compound. LCMS (ESI): m/z = 364.2 [M + 1] +. 0 Step B: 4-{4-(Trifluoromethyl)-1-[7-(trifluoromethyl)quinolin-3-vll]cyclohexyl}L phenol To phenol (52 mg, 0.55 mmol) dissolved in trifluoromethanesulfonic acid (0.60 mL) was added the title compound from the previous step (134 mg, 0.37 mmol). The mixture was stirred at room temperature for 16 h and quenched by slow addition of saturated aqueous NaHCO 3 . The resulting 5 mixture was extracted with EtOAc. The organic phase was concentrated and the residue was purified by silica gel chromatography eluting with a gradient of 0% to 60% EtOAc/hexanes to provide the title compound as a mixture of isomers. LCMS (ESI): m/z = 440.3 [M + 1]'. Step C: Butl 4-{4-(trifluoromethyl)- I -f7-(trifluoromethyl)quinolin-3y-vilcyclohexyl I benzoate ) To an anhydrous solution of the title compound from the previous step (80 mg, 0.18 mmol) in CH 2 C1 2 (2 mL) were added pyridine (0.022 mL, 0.27 mmol) and trifluoromethanesulfonic -61- WO 2007/111864 PCT/US2007/006806 anhydride (0.037 mL, 0.22 mmol). The mixture was stirred at room temperature for 20 min, quenched with water, and the crude product was extracted with EtOAc/hexanes. The organic phase was washed with H20 (2x) and brine, then dried over Na 2
SO
4 , and passed through a short silica plug. The filtrate was concentrated to dryness. The crude triflate was taken up in n-butanol (1.5 mL) and to the slurry was 5 added dichloro[ 1,1 '-bis(diphenylphosphino)ferrocene]palladium(II), dichloromethane adduct (14 mg, 0.018 mmol), and DIEA (0.10 mL, 0.57 mmol). The reaction mixture was stirred under CO (balloon) at 90 0C for 1 h. The resulting mixture was concentrated and purified by flash chromatography on silica gel eluting with a gradient of 16% to 50% EtOAc/hexanes to give the title compound as a mixture of isomers. LCMS (ESI): m/z = 524.3 [M + 1] . 0 Step D: N-(4-4-(Trifuoromethyl)--7-(trifluoromethyl)quinolin-3-v]clohexyl}benzoyl)-p-alanine, Isomers A and B To the title compound from the previous step (25 mg, 0.05) dissolved in a mixture of dioxane (0.4 mL) and MeOH (0.4 mL) was added NaOH (0.4 mL of a 3N solution). The mixture was 5 stirred at 60 0C for 1 h, allowed to cool to room temperature and acidified with 1 N aq. HCI. The aqueous phase was extracted with EtOAc, and the organic phase was washed with brine, dried over Na 2
SO
4 and concentrated in vacuo: LCMS (ESI): m/z = 468.1 [M + 1]+. To the crude carboxylic acid obtained above were added EDC (20 mg, 0.10 mmol), HOBt (16 mg, 0.10 mmol) and J3-alanine tert-butyl ester hydrochloride (19 mg, 0.10 mmol). The 3 combined solids were dissolved in DMF (0.80 mL), DIEA (0.028 mL, 0.16 mmol) was added, and the reaction mixture was stirred at 50 0C for 1 h. The reaction mixture was quenched by addition of water and the aqueous phase was extracted with EtOAc. The organic phase was washed with brine, dried over Na 2
SO
4 and concentrated in vacuo. The crude residue was then dissolved in CH 2 C1 2 (0.2 mL) and TFA (0.2 mL) was added. After 30 min, the mixture was concentrated in vacuo. Purification by reverse phase 5 1IHPLC (30% to 100% CH 3
CN/H
2 0, each with 0.05% (v/v) of TFA) provided the title compounds, with Isomer A as the faster-eluting product and Isomer B as the slower-eluting product. Isomer A: LCMS (ESI): m/z = 539.2 [M + H]. 'H NMR (500 MHz, d 6 -Acetone): 8 9.08 (s, 1 H), 8.77 (s, 1 H), 8.37 (s, 1 H), 8.31 (d, J= 8.5 Hz, 1 H), 7.89 (d, J= 8.5 Hz, 1 H), 7.82 (d, J= 8.7 Hz, 2 H), 7.78 7.73 (broad, 1 H), 7.49 (d, J = 6.9 Hz, 2 H), 3.64-3.58 (m, 2 H), 3.24 (d, J = 13.5 Hz, 2 H), 2.63(t, J = 6.9 SHz, 2H), 2.60-2.48(m, 1 H), 2.27 (d, J = 13.9 Hz, 2 H), 2.11-2.05 (min, 2H), 1.59 (quart, J = 12.1 Hz, 2 H). Isomer B: LCMS (ESI): m/z = 539.2 [M + H]
+
. 'H NMR (500 MHz, d 6 -Acetone): 5 8.99 (s, 1 H), 8.43 (s, 1 H), 8.33 (s, 1 H), 8.22 (d, J = 8.5 Hz, 1 H), 7.95 (d, J = 8.8 Hz, 2 H), 7.78-7.73 (mn, 2 H), 7.74 (d, J= 8.7 Hz, 2 H), 3.71-3.62 (min, 2 H), 3.22 (d, J = 13.3 Hz, 2 H), 2.68(t, J= 6.8 Hz, 2H), 2
.
60 -2.48(m, 1 H), 2.29 (d, J = 13.9 Hz, 2 H), 2.12-2.02 (m, 2H), 1.60 (quart, J= 12.1 Hz, 2 H). -62 - WO 2007/111864 PCT/US2007/006806 EXAMPLE 19 CI 0 F
F
3 C NH O 0 Step A: Methyl 4-(4-(trifluoromethyl)- 1- f4-F(trimethylsilvl)ethvnv11phenylleyvclohexyvlT)benzoate 5 To a solution of the title compound from Example 2, step A (200 mg, 0.39 mmol) in 1.2 mL of DMF was added trimethylsilylacetylene (0.085 mL, 0.59 mmol), bis(triphenylphosphine)palladium (II) chloride (83 mg, 0.12 mmol) and triethylamine (0.27 mL, 2.0 mmol). The mixture was stirred at 70 C under N 2 for 1 hour and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0% to 20% EtAOc/hexanes to provide the title compound. LC-MS 0 (ESI): m/z = 459.4 [M+I]* . Step B: 4-r[1-( 4 -Ethynylphenyl)-4-(trifluoromethyl)cyclohexyl]benzoic acid The title compound from the previous step (55 mg, 0.12 mmol) was dissolved in a mixture of 1,4-dioxane (2 mL) and LiOH (0.9 mL of a IN solution). The mixture was stirred at 40 °C for 5 1 hour. The solvents were removed in vacuo. The residue was acidified with 2N HCI (2 mL) and the resultant mixture was extracted with ethyl acetate (3 x 2 mL). The combined organic layer was reduced in vacuo to provide the product as a brown solid. LC-MS (ESI, neg. ion): m/z = 371.2 [M-1] ". Step C: tert-Butvl 3-(f4-f1-( 4 -ethvnvylphenyl)-4-(trifluoromethyl)cvclohexvllbenzovLyI}amino)propanoate ) To a solution of title compound from the previous step (44 mg, 0.118 mmol) in DMF (1 mL) was added (-alanine-tert-butyl ester hydrochloride (64 mg, 0.35 mmol), HOBt (54 mg, 0.35 mmol), EDC (91 mg, 0.47 mmol) and DIEA (0.31 mL, 1.8 mmol). The mixture was heated at 40 'C for 2 hours. The reaction mixture was diluted with 2 mL of ethyl acetate and washed with 2 mL of brine. The aqueous layer was extracted with ethyl acetate (2 x 2 mL). The organic layers were combined and dried S over Na 2
SO
4 . The solvent was removed in vacuo and the title compound was purified by flash chromatography on silica using a gradient of 0% to 50% EtOAc/hexanes, then 50% to 80% EtOAc/hexanes to provide the title compound. LC-MS (ESI): m/z = 444.4 [M - tert-Bu + 1] . - 63 - WO 2007/111864 PCT/US2007/006806 Step D: tert-Butvl 3-({4- [1-[4-(7-chloro-5-fluoro-1 -benzofuran-2-vyl)phenvll-4-(trifluoro methyl)cyclohexyl]benzovl } amino)propanoate To a solution title compound from the previous step (25 mg, 0.05 mmol) in DMF (0.5 mL] was added 2-chloro-4-fluoro-6-iodophenol (27 mg, 0.1 mmol), bis(triphenylphosphine)palladium (II) 5 dichloride (7 mg, 0.2 mmol), copper(I) iodide (1 mg, 0.1 mmol) and triethylamine (0.035 mL, 0.25 mmol) The reaction mixture was de-gassed in vacuo and was heated at 70 'C for 2 hours under N 2 , then allowed to stand at ambient temperature for 16 h. Purification by reverse phase HPLC using a gradient of 45% to 100 % MeCN/H 2 0, both containing 0.1 % TFA provided the title compound. LC-MS (ESI): m/z = 588.1 [M - tert-Bu + 1] . 0 Step E: 3-[({4-r[1-[4-(7-Chloro-5-fluoro-1-benzofuran-2-yl)phenvl-4-(trifluoromethy)cyclohexy] phenvl}l carbonvyl)aminolpropanoic acid The title compound from the previous step (4.9 mg, 0.0076 mmol) was dissolved in a solution of 50% (v/v) TFA in DCM with 2% H 2 0. The reaction mixture was allowed to stand at ambient 5 temperature for 45 min. The solvents were removed in vacuo and the residue was purified by reverse phase HPLC (45% to 100% MeCN/H 2 0, both containing 0.1 % TFA). LC-MS (ESI): m/z = 588.1 [M+I] +. 'H NMR (500 MHz, CD 3 OD): 6 (ppm) 7.82 (d, J= 8.5 Hz, 2H), 7.77 (d, J= 8.5 Hz, 2H), 7.57 (d, J= 8.1 Hz, 2H), 7.38 (d, J= 8.5 Hz, 2H), 7.26 (dd, J= 8.6, 2.5 Hz, 1H), 7.19 (s, 1f), 7.13 (dd, J= 8.9, 2.3 Hz, 1H), 3.63 (t, 3H), 2.95 (d, J= 13.3 Hz, 2H), 2.63 (t, 2H), 2.34 (m, 1H), 2.09-1.93 (overlapping m, 0 5H), 1.48 (m, 3H). The compounds in the following tables were prepared from Intermediates 1-11 using procedures similar to those described for Examples 1-19. Table 1 H R3a H 0 O N OH H Example R a LC-MS Example R a LC-MS -0 N 476.4 20 s 527.2 (M+1) 21 -o (M+1) 951.6 (2M+1) - 64 - WO 2007/111864 PCT/US2007/006806 22 -o ~. 470.3 (M+1) 23 cF4 939.5 23 CF3 554.3 (2M+1) (M+-) 24 cFz 538.3(M+1) 25 -o 484.3 (M+1) -o N -O N 26 513.2 (M+1) 27 521.3 -~ (M+I) Me 28 512.4 (M+1) 29 -oF 3 OC (M+1) 30 991.6 3 (2M+1) 3
OCF
3 524.3 496.4 (M+1) (M+1) 891.5 879.4 32 (2M+1) 33 1 (2M+1) 446.3 (M+I) 440.3 (M+I) 975.3 34 915.4 3 (2M+1) F (2M+1) 35 -o 448.2 458.3 (M+1) F (M+1) 36 °-o _ -,[ 548.1 c36 -0i 504.2 (M+1) 37 (M8.1) Br 550.3 (M+3) 8-0 CF 3 -0 ° c F 554.1 38 538.2 (M+1) 39-ocF) -0" c l -0 -q 40 - 538.2 (M+1) 41 538.2 cl 540.2 (M+3) F (M+1) 42 Me 454.3 (M+1) 43 c 474.2 -6(M+5) - 65 - WO 2007/111864 PCT/US2007/006806 44 I- -CF 3 508.2(M+1) 45 436.2 (M+I) 46 -4 484.3(M+1) 47 h 520. (M+1) 48 -o 510.2 (M+1) 49 526.2 (M+I) 50 -O 484.2(M+1) 51 -o490.2 I -o (M+1) -o - -o 00. 52 cN 495.2(M+1) 53 OMe 500.2 (M+1) 54 c c 538.1 (M+I) 55 508.2 c 540.1 (M+3) (M+I)
CF
3 56 524.2 (M+1) 57 - 472.2 522Me (M+1)
OCF
3 Me 58 F 488.2 (M+1) 59 OMe 470.2 MeO (M+1)
CF
3 60 576.2 (M+1) 61 - 482.2 (M+1)
CF
3 62 OiPr 498.2 (M+1) 63 470.2 (M+1) OMe 64 \- 474.2(M+1) 65 I- 474.2 C7. (M+1) cl cl F 66 524.1 (M+1) 67 476.2
F
3 CO (M+)F -66- WO 2007/111864 PCT/US2007/006806 CF 68 1 526.2 (M+1) 69 \ /OMe 4882 F (M+I) F 70 496.2 (M+1) 71 490.2 72 520.2 (M+) 73 (2M+1) 488.3 (M+1) -o .F c 538.2 74 75 (M+ 1) S506.3 (M+1) -c 540.2 (M+3) 76 -o (2M+) 77 cl 508.1 (M+1) 448.4 (M+1) c( F CI 78 F 476.2 (M+1) 79 OMe 504.1 cl 80 508.1 (M+1) 81 490.2 \ (M+1) 82 - -NO 2 485.2 (M+1) 83 480.2 o0 - (M4-1) 84 F 476.2 (M+1) 85 483.2 F (M+) 86 -"' 434.2 (M+1) 87 OiPr 516.3 Fq - (M+I) F 8 \- 465.2 (M4+1) 4 80.2 CN NN (M+I) 90>cN 645.2 (M+1) 91 -o 2.3 -7(M+) - 67 - WO 2007/111864 PCT/US2007/006806 92 422.3 (M+1) 93 - -SOzU 2 Me 518.3 (M+1) 94 /0--o ° 94459.3 (M+1) 95 0 512.3 (M+1) Table 2 X H, Rla H 0 R 2 a Example X Y R a
R
2a LC-MS m/z 96 o-HN H H s \ N 523.2 (M+I1) HN- N 97 H H -N.N N 983.6 (2M+1) HN-N 492.4 (M+I) 98 H H
/OCF
3 HNN 520.3 (M+1)
HN-
N HH - NN 883.5 (2M+1) HN-N 442.3 (M+1) 100C C -0 -HN , O H 556.2 (M+1) F 558.2 (M+3) 101 Cl Cl -- HN OH 488.2 (M+1) O 490.2 (M+3) - 68 - WO 2007/111864 PCT/US2007/006806 102 -HN v_ OH 502.2 (M+1) Cl Cl oo" cl C 0504.2 (M+3) 103 -HN.N..IOH 516.2 (M+1) C" I 0 518.2 (M+3) 104 -HN ... OH 544.2 (M+1) Cl C -o o 546.1 (M+3) 105 -HN, OH Cl H -o H 468.1 (M+1) 106 -HN'... OH Cl H -0-o o 510.2 (M+1) 107 -0 -HN'... OH CI H Fo 522.1 (M+1) F 108 -o F -HN. .OH Cl H o 522.1 (M+1) 109 C-0 F -HN OH 556.1 (M+1) C! CI o.. 558.0 (M+3) 110 -0 -HN rOH CI H cl o 538.1 (M+1) 111 C-o -HN OH 474.0 (M+3) 472.0 (M+1) 112 -HN OH Cl H 0o 496.2 (M+1) -69 - WO 2007/111864 PCT/US2007/006806 113 Cl H -- HN OH 456.2 (M+1) 0 456.2 (M+I) 114 , -7 OCF 3 -HN, OH CI H F - o 558.1 (M+1) 115 1y4 -HN..NOH Cl H o 530.4 (M+1) 116 -HN - .OH
-CH=CH
2 H o 502.3 (M+1) 117 -HN -,, OH
-CH=CH
2
-CH=CH
2 -0 - O 528.3 (M+1) 118 -HN OH 504.2 (M+1) Cl Cl -oo 506.2 (M+3) 119 -HN OH 518.2 (M+1) -Cl Cl -oo 520.2 (M+3) 120 Cl Cl -HN. OH 518.2 (M+1) 520.2 (M+3) 121 Cl CI -o c F -HN, OH 544.1 (M+1) 0 546.1 (M+3) 122 -HN OH 532.2 (M+1) 534.2 (M+3) - 70 - WO 2007/111864 PCT/US2007/006806 Table 3 R3a H R2a 0 Example R a
R
2a LC-MS m/z 123 -o -HN N HNNDN 523.2 (M+I) 124 -o -HN OH527.2 (M+1) 0 125
--
HN' OH 476.3 (M+1) 126 .- HN OH4.2 (M+1) o--OF 524.2 (VI+I) Table 4
F
3 C 3a 0 O N' OH H Example Isomer* R a LC-MS 127 127 A
-
544.3 (M+1) F 128 F A 544.3 (M+1) 129 A 532.3 (M+1) -71 - WO 2007/111864 PCT/US2007/006806 130 130 B .o 532.3 (M+1) 131 -o 1A 594.2 (M+1) CI 132 -oc B 594.2 (M+I) C, 133 I (--OCF3 133 A 580.3 (M+1) 134 A cI 530.3 (M+1) 135 5B -cI 530.3 (M+I) 136 o B 554.3 (M+1) 137 B - /CF 3 a 564.3 (M+I) 138 B 552.3 (M+1) 139 B 532.3 (M+1) F 140 B 536.3 (M+1) 141 B c 564.2 (M+1) CI 142 1 B 546.3 (M+1) - 72 - WO 2007/111864 PCT/US2007/006806 143 143 B -- CN 521.3 (M+1) 144 Oae 144 B /So 2 Me 574.2 (M+1) 145 B 562.4 (M+1) 146 [ - -N 146 B \ NO 2 541.3 (M+1) 147
/-
147 B - .
500.3 (M+1) 148/- 148 B 502.4 (M+I1) 149 B 502.4 (M+I) 150 B OMe 576.4 (M+1) 151 151 B OMe 560.3 (M+1) CI 152 15B - Me 510.3 (M+1) 153 B 15 B_ Et 524.3 (M+I1) 154 B )538.4 (M+1) 155 B 530.3 (M+I) CI cl- 73 - 73 - WO 2007/111864 PCT/US2007/006806 156 _ 156 B \) cl 564.3 (M+I) CI 157 _ 15B 532.4 (M+1) F F CI 158 B 564.3 (M+1) Cl 159 -N 159 B 547.4(M+1) 160 B 547.3 (M+1) 161 0' \ N 161 B 515.4 (M+1) 162 -o B 527.2 (M+1) 163 -o 163 B 527.2 (M+1) 164 B 0o 4B -o /CF 584.2 (M+1) 165 B N 577.2 (M+1) B 583.2 (M+1) 167 I 167 B F 544.4 (M+1) MeO - 74 - WO 2007/111864 PCT/US2007/006806 168 B F 515.4 (M+1) 169 169 B cl 580.1 (M+1) 170 -N 170 B o 527.4 (M+1) MeO 171 B 560.4 (M+1) CI 172 _ 172 B 544.4 (M+1) OMe 173 B 570.4 (M+1) 174 174 B
-
- O cF 3 614.3 (M+1) CI 175 B 553.3 (M+1) 176B 536.4 (M+1) 177 B -N 536.3 (M+1) 178 B 554.4 (M+1) N 179 B 552.4 (M+1) - 75 - WO 2007/111864 PCT/US2007/006806 180 B 538.4 (M+1) -'o N 181 B 538.4 (M+I1) 182 B 586.4 (M+1) 183B 602.4 (M+1) B 184 B Neg. ion: 549.4 (M-1)" F 185 -/ SB 544.4 (M+1) MeO
CF
3 186 186B 582.4 (M+1) F 187 B a 574.4 (M+1) EtO 188 CI Neg. ion: B N 567.4 (M-I) H 189 B N tN u 544.4 (M+1) O'"tBu 190 - ,-- a 190 B I /CF 3 598.4 (M+1) CI 19 ! -/ cI 191 B c 574.4 (M+1) EtO - 76 - WO 2007/111864 PCT/US2007/006806 192 _ 192 B oPr 588.4 (M+1) CI 193 B ci 531.1 (M+1) N OMe 194 B 556.4 (M+1) MeO 195B - /OMe 526.4 (M+1) 196 OMe B 526.4 (M+1) 197 B 9 527.1 (M+1) MeO 198 B \515.4 (M+I) F 199/ B )-oMe 528.1 (M+1) N Br 200 B N 605.1 (M+1) MeO 201 B
N-
F3 565.2 (M+I) 202 B 537.1 (M+1) 203 N 203 B cF 3 565.2 (M+1) - 77 - WO 2007/111864 PCT/US2007/006806 CI 204 B \ 544.4 (M+1) 205 l 20B 544.4 (M+1) CI 206 B 531.4 (M+I) cI 207 207 B N 531.4 (M+1) CI CI 208 B \ / 548.4 (M+1) F 209 209 B 548.4 (M+1) F CI 210 210 B 564.4 (M+1) CI Cl 211 . OMe B N 557.4 (M+1) MeO 212B OMe Neg. ion: H 563.4 (M-1) 213 CN B N Neg. ion: 558.3 (M-l) H OMe 214 B 545.4 (M+I) F 215 B / 565.3 (M+1) -78 - 78 - WO 2007/111864 PCT/US2007/006806 216 B \ 614.4 (M+1) FsCO 217 _______________Me____ 217 Me540.5 (M + ) MeO 217 _ C 21 B 561.40.5 (M+1) MeO 218 C B /561.4 (M+1) -N 219 F OMe B 544.4 (M+1) 220 B \ / 598.4 (M+1) CI 221 B -_ B 540.5 (M+1) 222 B 571.3 (M+1) C I 223-c B \ / 588.4 (M+1) PrO 224 - c 224 B CI 560.4 (M+1) MeO 225 Me B I 551.4 (M+1) 226 -N B - / -CF 3 565.4 (M+1) 227 B 568.5 (M+1) 7MeO9 -79 - WO 2007/111864 PCT/US2007/006806 228 B 619.5 (M+1)
F
3 C 229 B N 565.5 (M+1) 230 I-N B 581.5 (M+1) OMe 231 -N / B .540.5 (M+1) 232 CF 3 232 B cF 604.2 (M+1) 233 / ,CN B c 561.2 (M+1) CF, 234 B 594.4 (M+1) MeO F 235 F 23B 1 F 562.4 (M+1) MeO 236 NO, 236 B No 2 582.2 (M+1) 237 B /7 563.4 (M+1) 0 -N 238 B 2 552.4 (M+1) -80- WO 2007/111864 PCT/US2007/006806 239 B 561.4 (M+1) * Isomer A corresponds to the product derived from Intermediate 5, Isomer A: Isomer B corresponds to the product derived from Intermediate 5, Isomer B. Table 5 CI R"a
F
3 C CI 0 O N OH H Example R 3 a LC-MS 20-o 612.0 (M+1) 241 - OMe 624.1 (M+1) 242 -O F- 612.1 (M+I) 243 -o560.3 (M+1) 244F 612.3 (M+1) 245 - 5 24-oc 630.2 (M+1) 246 246 -oN 636.3 (M+1) - 81 - WO 2007/111864 PCT/US2007/006806 Table 6
F
3 C N R3a 0 O N OH H Example Isomer* R LC-MS 247 c 24A 561.3 (M+1) MeO 248 /C 24B 561.3 (M+1) MeO 249 }c 249 A c 531.3 (M+1) 250 B c I 531.3 (M+1) 251 B 0 2537.3 (M+1) 252 B 1-
-
OCF
3 581.4 (M+1) 253 B 565.3 (M+1) CI 254_ s/ 254 B 571.4 (M+1) 255_ 25B 565.3 (M+1) CI -82 - WO 2007/111864 PCT/US2007/006806 256 - /OMe 256 B 'e577.4 (M+1) 257 B c 257 B c 570.3 (M+1) H 258 B 599.3 (M+1) cI 259 B i -- CF 3 565.3 (M+1) 260/= B / 553.3 (M+1) 261 cl B /C 561.3 (M+1) MeO
CF
3 2 2B 1 - 633.6 0M+ 1) 262 B \ / 633.6 (M+1)
_____________CF
3 263 B 553.3 (M+1) S CI 264 - /Cl. 264 B 581.6 (M+1) - /Cl 265 I c 265B N 582.3 (M+1)
CF
3 266 /-4 6164 (+ 2676 B N 616.4 (M+1) 267 B OCF 631.3 (M+I) - 83 - WO 2007/111864 PCT/US2007/006806 268 B - 2548.2 (M+1) 269 269 B 547.4 (M+1)
N
270 270 B 548.3 (M+1) * Isomer A corresponds to the product derived from Intermediate 10, Isomer A. Isomer B corresponds to the product derived from Intermediate 10, Isomer B. Table 7
R
3a
F
3 C O N - OH H Example Isomer* R a LC-MS 271 A -OMe 500.3 (M+1) 272 B -OMe 500.3 (M+1) 273 A OCF3 Neg. ion: 629.2 (M-1) 274 A - 554.4 (M+1) 275 A -o 542.4 (M+1) 27A -- OMe 610.4 (M+1) C 8 - 84 - WO 2007/111864 PCT/US2007/006806 277 A 2 586.3 (M+1) CI 278 A 614.2 (M+I) CI 279 A -o 514.3 (M+1) 280 A -o 528.3 (M+1) 281 -o - F 281 A
-
594.4 (M+1) 282 A -o 542.1 (M+1) 283 A -o 556.5 (M+1) 284 A -o 528.3 (M+1) Poor ionization: 'H NMR of aromatic region (500 MHz, acetone-d 6 ): 8 8.20 (s, 1H), 285 8.08 (br, 2H), 8.00 (d, J= 8.7 Hz, 285 A 1H), 7.93-7.85 (m, 5H), 7.80 (t,
OCF
3 1H), 7.74 (m, 2H), 7.65 (d, J= 8.5 Hz, 2H), 7.45 (dd, J= 8.7, 2.1 Hz, 1H). 286 -O
CF
3 A -c 644.4 (M+1) 287 287 A - F 612.2 (M+1) - 85 - WO 2007/111864 PCT/US2007/006806 288 F 288 A P CF , 648.3 (M+1) Cl 289 A_ F 289 A 582.6 (M+I) F 290 c l 0A c 619.2 (M+I) H 291 _ c 291 A C 614.2 (M+1) Cl 292 -0 -
OC
F
3 A 660.2 (M+1) 293 A -o554.3 (M+1) 294 -o c A .- c610.2 (M+1) 295 _0 A 582.3 (M+1) 296 -N 7A 581.4(M+1) 297 A 581.4 (M+1) CI F 298 A582.4 (M+1) Cl 299 _ A 299F 598.3 (M+1) CI 300 A N 581.5 (M+1) - 86 - WO 2007/111864 PCT/US2007/006806 301CF 301 A cl 648.2 (M+1) 302_ 302 A \ 614.2 (M+1) CI Cl CI 303 A -4)614.1 (M+1) F 304 A 3 /564.2 (M+1) 305 -o N A - ci 610.3 (M+1) 306 A - OMe 577.4 (M+1) N 307 A -CH2 F 592.3 (M+1) 308 A -pentyl 540.3 (M+1) 309 A -CH2- Neg. ion: 578.5 (M-1) 310 A -/OMe 579.6 (M+1) F 311 A N 565.7 (M+1) 312- / 312 A N 590.7 (M+1) OMe 313 A N 595.7 (M+1) F 87 -87 - WO 2007/111864 PCT/US2007/006806 314 cl A 580.0 (M+1) 315 Me A 35F 578.5 (M+1) 316 A 588.2 (M+I) 317 A - N 550.4 (M+1) 318 A s 552.3 (M+1) 319 A _ o 536.2 (M+1) 320 0 A 565.4 (M+I) 321 A
-
538.3 (M+I1) 322 A - 552.3 (M+1) 323 A -OCF 2 H 536.1 (M+I1) * Isomer A corresponds to the product derived from Intermediate 8, Isomer A. Isomer B corresponds to the product derived from Intermediate 8, Isomer B. - 88 - WO 2007/111864 PCT/US2007/006806 Table 8 N R 3 a
F
3 C N.
-
R 3a 0 0 W- - OH O N OH H Example isomer* a LC-MS 324 A -OMe 501.3 (M+1) 325 B -OMe 501.3 (M+1) 326 A -OPr 529.3 (M+1) 327 B -OPr 529.2 (M+1) 328 A -OBu 543.3 (M+1) 329 B -OBu 543.3 (M+1) 330 A -o555.4 (M+1) 331 B 555.4 (M+1) 332 A - 613.4 (M+1) -89- WO 2007/111864 PCT/US2007/006806 333 -0 F B F 613.3 (M+1) 334 - ,- , 334 A CI 615.2 (M+1) Cl 335 F 335 A F 583.2 (M+1) F 336 -H 336 A -CH 2 581.3 (M+1) 337 A -n-pentyl 541.3 (M+1) 338 A -n-hexyl 555.4 (M+1) 39A - 583.3 (M+1) F 39A \ / 583.3 (M+1) 340 l 340 A 615.2 (M+1) CI 341 341 A 581.3 (M+1) Cl 342 342 A 565.2 (M+1) F 343 343A -o 529.3 (M+1) 344 A 555.3 (M+1) 345 - F 345 A 593.3 (M+1) -90 - WO 2007/111864 PCT/US2007/006806 346 -OH 2 346 A -CH575.3 (M+1) 347 -OH 2 347 A 593.3 (M+1) 348 A 631.4 (M+1)
OCF
3 349 A
CF
3 649.3 (M+1) CI A CF649.4(M+1)
CF
3 351 - F 351 A F 599.4 (M+1) ci * Isomer A corresponds to the product derived from Intermediate 9, Isomer A. Isomer B corresponds to the product derived from Intermediate 9, Isomer B. Table 9
F
3 C A
R
M 0 o) O N 'OH H Example >R 3a LC-MS 352 ~\ 352 500.2 (M+1) 3530 353
-
554.2 (M+1) F -91- WO 2007/111864 PCT/US2007/006806 354 1),o 502.1 (M+1) CI 355 / 536.1 (M+1) 356 N356 555.3 (M+1) F 357 o N 621.3 (M+1)
OCF
3 358 516.3 (M+1) 359 516.2 (M+1) 3600 360 564.2 (M+1) 361 566.2 (M+1) 362 _/ OBu 625.3 (M+23) CI 363 542.4 (M+1) 364 / 6 -F 554.4 (M+1) - 92 - WO 2007/111864 PCT/US2007/006806 365 365 o 572.5 (M+1) Pr Pr CI 366 / - 588.2 (M+1) F 0 367 592.3 (M+1) 368 . NEt 2 545.3 (M+1) 369 516.3 (M+1) 370 \/ 518.3 (M+1) 371 \ o 530.1 (M+1) Pr 372 0 372 o 544.1 (M+1) Et Et Table 10 R, R"a R' 1 0 O N OH H Example Isomer R',R" a LC-MS - 93 - WO 2007/111864 PCT/US2007/006806 373 A* H, t-Bu s 571.1 (M+1) 374 B* H, t-Bu S 571.1 (M+l) 375 A* H, Ph 591.1 (M+l) 376 376 B* H, Ph 591.1 (M+1) 377 Me, Me F- /OCF 3 540.2 (M+1) 378 -0 ;_1 378 A* H, t-Bu F 532.2 (M+1) 379 B* H, t-Bu -o F 532.2 (M+1) 380 B** H, t-Bu - 518.2 (M+1) 381 A** H, t-Bu 1c 518.2 (M+1) 382 A*** H, t-Bu i--/OCF 3 568.4 (M+1) 383 B*** H, t-Bu F- /OCF 3 568.4 (M+1) 384 B** H, t-Bu - 520.4 (M+1) * Isomer A is the faster-eluting isomer and Isomer B is the slower-eluting isomer by reverse-phase HPLC (Cl 8, MeCN/H 2 0 gradient, each containing 1% (v/v) of TFA) - 94 - WO 2007/111864 PCT/US2007/006806 ** Isomer A is the faster-eluting isomer and Isomer B is the slower-eluting isomer by chiral HPLC (OJ column, 10% EtOH/heptane) *** Isomer A is the faster-eluting isomer and Isomer B is the slower-eluting isomer by chiral HPLC (OC column, 10% EtOH/heptane) 5 Table 11 R3a 0 O N OH H Example n R a LC-MS 385 -o 3 S / 515.2 (M+1) 386 1-occl 498.2 (M+1) 387 1 o--°CFa 482.1 (M+1) 388 1\/ci 432.1 (M+I1) 389 I1 454.2 (M+I) 390 2 470.3 (M+1) 391 2 \/ci 448.2 (M+1) 392 2 - CF 3 482.3 (M+1) -95 - WO 2007/111864 PCT/US2007/006806 Table 12
R
3 a O N OH H Example n R LC-MS 393 Neg. ion 2 530.2 (M-1) 394 2 - OCF 3 Neg. ion 558.2 (M-1) 395 2 c Neg. ion 508.1 (M-1) 396 396 1 518.2 (M+1) 397 397 1 / c 496.3 (M+I) BIOLOGICAL ASSAYS The ability of the compounds of the present invention to inhibit the binding of glucagon 5 and their utility in treating or preventing type 2 diabetes mellitus and the related conditions can be demonstrated by the following in vitro assays. Glucagon Receptor Binding Assay A stable CHO (Chinese hamster ovary) cell line expressing cloned human glucagon D receptor was maintained as described (Chicchi et al. J Biol Chem 272, 7765-9(1997); Cascieri et al. J Biol Chem 274, 8694-7(1999)). To determine antagonistic binding affinity of compounds 0.002 mg of cell membranes from these cells were incubated with 2 5 s1-Glucagon (New England Nuclear, MA) in a buffer containing 50mM Tris-HCI (pH 7.5), 5mM MgCI,, 2mM EDTA, 12% Glycerol, and 0.200 mg WGA coated PVT SPA beads (Amersham), +/- compounds or 0.001 MM unlabeled glucagon. After 4-12 - 96 - WO 2007/111864 PCT/US2007/006806 hours incubation at room temperature, the radioactivity bound to the cell membranes was determined in a radioactive emission detection counter (Wallac-Microbeta). Data was analyzed using the software program Prism' from GraphPad. The IC 5 0 values were calculated using non-linear regression analysis assuming single site competition. ICs 50 values for the compounds of the invention are generally in the rangte of as low as about 1 nM to as high as about 500nM, and thus have utility as glucagon antagonists. Inhibition of Glucagon-stimulated Intracellular cAMP Formation Exponentially growing CHO cells expressing human glucagon receptor were harvested with the aid of enzyme-free dissociation media (Specialty Media), pelleted at low speed, and re S suspended in the Cell Stimulation Buffer included in the Flash Plate cAMP kit (New England Nuclear, SMP0004A). The adenylate cyclase assay was setup as per manufacturer instructions. Briefly, compounds were diluted from stocks in DMSO and added to cells at a final DMSO concentration of 5%. Cells prepared as above were preincubated in flash plates coated with anti-cAMP antibodies (NEN) in presence of compounds or DMSO controls for 30 minutes, and then stimulated with glucagon (250 pM) S for an additional 30 minutes. The cell stimulation was stopped by addition of equal amount of a detection buffer containing lysis buffer as well as 1 2 sI-labeled cAMP tracer (NEN). After 3 hours of incubation at room temperature the bound radioactivity was determined in a liquid scintillation counter (TopCount Packard Instruments). Basal activity (100% inhibition) was determined using the DMSO control while 0% inhibition was defined at the amount of pmol cAMP produced by 250pM glucagon. ) Certain embodiments of the invention has been described in detail; however, numerous other embodiments are contemplated as falling within the invention. Thus, the claims are not limited to the specific embodiments described herein. All patents, patent applications and publications that are cited herein are hereby incorporated by reference in their entirety. -97-

Claims (15)

  1. 2. A compound in accordance with claim 1 wherein Ring A represents an Aryl group selected from phenyl, naphthyl and tetrahydronaphthyl, a HAR group which is a 6-10 membered aromatic heteroaryl or partially aromatic hetercyclyl containing 1-2 heteroatoms, 0-1 of which is O and 0 2 of which are N atoms. 5
  2. 3. A compound in accordance with claim 2 wherein Ring A represents a member selected from the group consisting of:
  3. 4. A compound in accordance with claim 3 wherein Ring A represents a member 0 selected from the group consisting of: NO N 0H
  4. 5. A compound in accordance with claim 1 wherein n represents an integer selected from 1, 2 and 3.
  5. 6. A compound in accordance with claim 5 wherein n represents an integer selected 5 from I and 2.
  6. 7. A compound in accordance with claim 6 wherein n represents 2..
  7. 8. A compound in accordance with claim 1 wherein the R1 and R2 groups represent hydrogen or 1-2 of the R' and R 2 groups are independently selected from the group consisting of: halo; OH; CI-6alkyl optionally substituted with 1-3 halo groups; CN; NR 6 R'; SOpRs; C 2 .4alkenyl, and a 6-10 -99 - WO 2007/111864 PCT/US2007/006806 membered Aryl group, or the R2 groups are taken in combination and represent a -CH 2 - or -CH 2 CH 2 group, or a fused phenyl ring, unsubstituted or substituted with 1-3 groups, up to 3 of which are halo groups, and up to 2 of which are CI- 3 alkyl, haloCI. 3 alkyl, C 1 . 3 alkoxy or haloCI-. 3 alkoxy groups. 5 9. A compound in accordance with claim 8 wherein the R' groups represent hydrogen halo; C. 3 alkyl optionally substituted with 1-3 halo groups; CN or NR 6 R 7 ; and the R 2 groups represent H, or are taken in combination and represent a -CH 2 - or a fused phenyl ring, unsubstituted or substituted with 1-3 groups, up to 3 of which are halo groups, and up to 2 of which are C 1 . 3 alkyl, haloC_ 3 alkyl, CI- 3 alkoxy or haloC 1 . 3 alkoxy groups. 0
  8. 10. A compound in accordance with claim 9 wherein the R' groups represent hydrogen, halo; CH 3 or CF 3 , and the R2 groups represent H, or are taken in combination and represent a -CH2- or a fused phenyl ring. 5 11. A compound in accordance with claim 1 wherein R a is selected from N ,/\.CO 2 H and /N HN-N
  9. 12. A compound in accordance with claim 11 wherein R represents ,- CO2H
  10. 13. A compound in accordance with claim 1 wherein Rb represents H. 0 14. A compound in accordance with claim 1 wherein each R is selected as follows: 1) 0-1 R 3 group is selected from the group consisting of: Aryl, HAR, -CH 2 -Aryl, -CH2 -HAR, -O-Aryl, -O-HAR, -O-CH 2 -Aryl and -O-CH 2 -HAR; said Aryl and HAR groups and portions of the groups above being optionally substituted with 1-2 halo atoms, and 1-2 members selected from: CN, C 1 -alkyl, OC 1 ealkyl, haloC. 5 3 alkyl, OCI. 3 haloalkyl, NO 2 , S(O)pR 5 , C 2 -6alkenyl, NH2, NMe 2 and HAR; 2) 0-3 R 3 groups are selected from: CN, oxo, NO 2 , S(O),CI.salkyl, NH 2 , NMe 2 , CI. 7 alkyl, haloCs. 3 alkyl, OC. 7 alkyl, OCi. 3 haloalkyl and C 2 -6alkenyl, and 3) the remaining R groups are H or halo atoms. 0 15. A compound in accordance with claim 14 wherein each R is selected as follows: 1) 0-1 R group is selected from the group consisting of: Aryl, HAR, -CH 2 -Aryl, -CH 2 -HAR, -O-Aryl, -O-HAR, -O-CH 2 -Aryl and -O-CH 2 -HAR; said Aryl and HAR groups and portions of the groups above being optionally substituted with 1-2 halo atoms and 1-2 members selected from: CN, Cl_ 4 alkyl, OCI_6alkyl, S(O)pC. 5 6 alkyl, halomethyl, halomethoxy, NO 2 , NMe 2 and pyrazolyl; - 100- WO 2007/111864 PCT/US2007/006806 2) 0-1 R 3 group is selected from: CN, oxo, NO 2 , SO 2 CH 3 , NMe 2 , CI- 7 alkyl, haloCI. 3 alkyl, OCI. 7 alkyl, OCI. 3 haloalkyl and C 2 6alkenyl,and 3) the remaining R' groups are H or halo atoms. S
  11. 16. A compound in accordance with claim 15 wherein each R is selected as follows: 1) 0-1 R 3 group represents: Aryl, wherein Aryl is selected from phenyl, naphthyl and tetrahydronaphthyl; HAR selected from pyridyl, quinolinyl, pyrimidinyl, isoxazolyl, benzoxazolyl, benzopyrazolyl, benzooxadiazolyl, indazolyl, benzofuranyl, tetrahydroquinolinyl, benzothiophene, benzothiazole and benzoimidazolyl; -CH 2 -Aryl selected from benzyl; -O-Aryl 0 selected from phenyloxy; -O-HAR selected from pyridyloxy, benzothiazoloxy and quinolinyloxy; -0 CH 2 -Aryl selected from benzyloxy or -O-CH 2 -HAR selected from: pyridylmethoxy, furanylmethoxy, benzothiazolmethoxy and quinolinylmethoxy, said Aryl and HAR groups and portions of the groups above being optionally substituted with 1-2 halo atoms and 1 member selected from: CN, C 1 4alkyl, methoxy, trifluoromethyl, 5 trifluoromethoxy, NO 2 , and NMe 2 ; 2) 0-1 R group is selected from: CI-7alkyl, haloC. 3 alkyl, OCI.- 7 alkyl and OC. 3 haloalkyl, and 3) the remaining R 3 groups are H or halo atoms. O
  12. 17. A compound in accordance with claim 1 wherein: Ring A represents an Aryl group selected from phenyl, naphthyl and tetrahydronaphthyl, a HAR group which is a 6-10 membered aromatic heteroaryl or partially aromatic hetercyclyl containing 1-2 heteroatoms, 0-1 of which is O and 0-2 of which are N atoms; n represents an integer selected from 1, 2 and 3; 5 the R' and R2 groups represent hydrogen or 1-2 of the R' and R 2 groups are independently selected from the group consisting of: halo; OH; Ci-6alkyl optionally substituted with 1-3 halo groups; CN; N'RR 7 ; SOpR 5 ; C 2 4alkenyl, and a 6-10 membered Aryl group, or the R2 groups are taken in combination and represent a -CHz- or -CH 2 CH 2 - group, or a fused phenyl ring, unsubstituted or substituted with 1-3 groups, up to 3 of which are halo groups, and up to 2 of which are CI. 3 alkyl, ) haloC 1 . 3 alkyl, Ci. 3 alkoxy or haloCI. 3 alkoxy groups; R a is selected from N C O 2H and HN-N Rb represents H, and each R 3 is selected as follows: 2) 0-1 R 3 group is selected from the group consisting of: Aryl, HAR, -CH 2 -Aryl, -CH 2 -HAR, -O-Aryl, -O-HAR, -O-CH 2 -Aryl and -O-CH 2 -HAR; - 101 - WO 2007/111864 PCT/US2007/006806 said Aryl and HAR groups and portions of the groups above being optionally substituted with 1-2 halo atoms, and 1-2 members selected from: CN, Cs_6alkyl, OCI-6alkyl, haloC 3 alkyI, OCI. 3 haloalkyl, NO 2 , SOpR s , C 2 . 6 alkenyl, NH 2 , NMe 2 and HAR; 2) 0-3 R 3 groups are selected from: CN, oxo, NO 2 , S(O)pC.s 8 alkyl, NH 2 , NMe 2 , C 1 _ 7 alkyl, haloCI. 3 alkyl, OC1. 7 alkyl, OCI. 3 haloalkyl and C 2 6 alkenyl, and 3) the remaining R 3 groups are H or halo atoms.
  13. 18. A compound selected from the following tables: F F 3 C FF FC F o O N ' OH H 0 N OH H OCF 3 CI F 3 C F 3 C CF3 NII 0 0 O OH 0 N OH H F F 3 C FC 0 0 O N -OH 0 N -> OH H H -102 - WO 2007/111864 PCT/US2007/006806 CI F 3 C 0,- F3 00 o N' H 0N''O HH cI Br FC - 0 -'I H r_. ^ 0 N- OH H Br CN 00 0 0 N O H O N O-" H H 0 F 3 C -0 FsC 0 0 N'0 N"*'0H 0 H 0 N" OH - 103 - WO 2007/111864 PCT/US2007/006806 MeN OCF 3 O OCF, FCC - yNH - H N O OH - 104 O NH CO2H H F CFz FC\ ,N OH F3C H H N /N ,-OH H O 0 CI 0 /F F 3 C OH NH 0 Table I R / 0 0 N OH H Example R 3 " Example R - 104- WO 2007/111864 PCT/US2007/006806 20 o 21 o 22 23 oCF 3 24 CF3 25 -o - 0 N -o N 26 27 Me
  14. 28-o 29 -0 oe 28 29 "O"a OCF 3 30 31 32 33 F 5 -0 34 35 F -0 -~ -0 36 ci 37 Br ~ .CF 3 -0 OCF 3 38 39 40 41 F 3 C Cl 42 -O -Me 43 ci -105- WO 2007/111864 PCT/US2007/006806 44 -O -CF 3 4 46 Me 47 48 -r49 50 C' 51 52 ON 53 OMe 54 -0 C 55 CF 3 56 IP5 - OCF 3 Me 58 1- F 59 0-e Med CF 3 60 -361 62 Oir63 OMe 64 65 Q F 66 67 F 3 CO F -106 - WO 2007/111864 PCT/US2007/006806 CF 3 68 c69 \ o-s F FC 78 I- F 79 1" o u e , F C 80 - , 81 74 75 c!l F FC 78 ~ \F79 ~ \ome 86 871 82 83 0 84 ~ \ F85 FF 86 87 \/ -OiPr F 88 CN 89 H 90 / CN 91 - 107 - WO 2007/111864 PCT/US2007/006806 -o/ l_ so2M e 92 93 94 -N 95 - 0 Table 2 R 3a R R 3 b /~ R3c O0 Ral Example R3a R R 3 b Ral H H _O'y- N -HN N 96 s/\NH HN- N 97 H H -HN YN 97 " HN- N H H -HNN 98 YOCF 3 "M HN-N 100 Cl CI -HN OH 100~ -'' "NaF O FO 101 CI CI -HN OH 0- 108 - 108 - WO 2007/111864 PCT/US2007/006806 102 cI CI -HN OH 0 13CI CI -HN --- IOH 103 104 CI CI -O HN ->.OH 105 cI H -HN OH 0 106 CI HH -Oy HN OH 107 CI H -0 - HN --- yOH CI H F -N O
  15. 108-o - H~O 10 CI H -0 F~ -HN --- yOH CI 0 CI CI -01- -HN ~OH cI 0 112 lH-HN -OH 113 CI H -HN -- yOH 0 114 cl / _a OCF 3 -HN-<OH - 109 - WO 2007/111864 PCT/US2007/006806 115 CI H 1-04 -HN OH 0 116 -CH=CH 2 H-N- O 0 117 -CH=CH 2 -CH=CH 2 -HN-_OH 0 118 CI ciHN >OH 0 119 CI CI -HN OH 0 120 CI CI HN O 0 121 CI cl_ -,,F HN OH 121 0 122 clc HN OH 0 Table 3 0 R 1 Example R~b a -110- WO 2007/111864 PCT/US2007/006806 123 - -HNr N 124 -0 -HN OH 0 125 -HN, OH 0 126 i /-OCF3 -HN < OH o Table 4 F 3 C R3a o O N OH H Example Isomer R 3 a Example Isomer* R 3a 127 A 128 A F F 129 A 130 B 1 3 1 A c l 1 3 2 B c I cf ci - ci 133 A I O CF 134 A 151c 135 B c136 B - 111 - WO 2007/111864 PCT/US2007/006806 137 B F 138 B 139 B 140 B F 141 B 142 B \/ C CI 143 B c 144 B So2Me cN 145 B - 146 B 147 B 148 B 149 B 150 B oe 151 B oMe 152 B CI 153 B Et 154 B 155 B 156 Bc CI CI 157 B I 158 B C_ I: F CI 159 B N 160 B -112- WO 2007/111864 PCT/US2007/006806 161 B 162 B /0 -0 165 B 166 B -0 16 B 0CF 3 N 165 B 166B 167 B 168 B F F N MeO 169 B -170 B -N 171 B Mo 172 B F CI OMe 173 B 174 B c! 175 B 176 B 177 B 178 B 179 180 B \ N 181 B 182 B -113- WO 2007/111864 PCT/US2007/006806 183 B 0 184 B 185 B F 186 B F MeO F 187 B 188 Bc N H EtO 189 B N 190 B S tu CF 3 CI 191 B - 192 B cI /OPr EtO c, ie. 193 B 194 B oMe C I cnz MeO 195 B )- -OMe 196 B oMe 197 B 198 B N N MeO F 199 B 200 B N 1\ N MeO 201 B CFa 202 B ,N 203 B N- 204 B c S/ CF 3 205 B - 206 B I CI -114- WO 2007/111864 PCT/US2007/006806 207 B 208 B ci 209 B 210 B F Ci ci ci 211 B212 B -, OMe OMe/ NN 213 B 1 CN 214 B OMe H -0 F 215 B CI216 B C Ci F 3 CO_ 217 B Me 218 B ci ____ Me MOO 219 BF OMe 220 B CF, ci 221 B 222 B N 223 B ci224 B MOO pro 225 BMe 226 N I~~ ~ ~ ~ / (0] CF 3 0 N 227 B 228 13 Mao FSC WO 2007/111864 PCT/US2007/006806 229 B 230 B OMe 231 B N 232 B CF 3 \-/N /' 233 B CN 0 234 B CF 3 235 B F F Meoo MeO 236 B No 2 237 B 0 -N 238 B 239 B Table 5 CI FaC R3a CI 0 o O N OH H Example R 3 a Example R 3 a 240 oF 241 -o - o e -116- WO 2007/111864 PCT/US2007/006806 242 -O243 0 244 -o 245 -0c F cI 246 -o 10 N Table 6 F 3 C N R 3a 0 O N OH H Example Isomer* R 3a 247 A ci MeO 248 B ci MeO 249 A 250 B -117- WO 2007/111864 PCT/US2007/006806 251 B 252 B - -bCF 253 B 1 C 254 B 255 B c CI 256 B OMe -/ 257 B c l H 258 B I-- CF 3 CI 259 B 1 / CF 3 260 B 261 B MeO 262 B CF 3 CF 3 263 B -118- WO 2007/111864 PCT/US2007/006806 264 B ci 265 B CA N 266 B CF 3 N 267 B - / OC F 3 268 B N 269 B 270 B Table 7 F 3 C" R FsC 0 O NAOH H Example Isomer* R 271 A -OMe 272 B -OMe -119- WO 2007/111864 PCT/US2007/006806 273 A -- OCF 3 274 A -o 275 A 276 A o Me CI 277 A Cl 278 A Cl 279 A o 280 A -o F 281 A -0 282 A 283 A 284 A o 285 A OCF 3 - 120- WO 2007/111864 PCT/US2007/006806 286 A -O ~ CF 3 287 A -o0 F 288 A __ CF 3 Cl 289 A IF F 290 A ., c s H 291 A \- cl CI 292 A -o ]OCF 3 293 A 294 A -o c l 295 A -o 296 A -N 297 A CIl F 298 A -121 - WO 2007/111864 PCT/US2007/006806 Cl 299 A 16F 300 A -d_ Nl CF, 300 A 301 A CF 3 cl CI 302 A •Cl Cl CI 303 A c c F 304 A 305 A -o -Ncl CI 306 A /,OMe N 307 A -CH 2 - F 308 A -pentyl 309 A -CH 2 310 A oN)_O e N F 311 A - 122- WO 2007/111864 PCT/US2007/006806 312 A 313 A OMe /N F 314 A cIl 315 A Me 316 A 317 A N 318 A 319 A 320 A 0 SN' 321 A 1-0 322 A 323 A -OCF 2 H - 123 - WO 2007/111864 PCT/US2007/006806 Table 8 N R F 3 C 0 (-) o O N'-J OH H Example Isomer* R 324 A -OMe 325 B -OMe 326 A -OPr 327 B -OPr 328 A -OBu 329 B -OBu 330 A 331 B 332 A -o0 F F 333 B -0 F F124 - 124 - WO 2007/111864 PCT/US2007/006806 334 A c CI 335 A -- F F 336 A -c' 337 A -n-pentyl 338 A -n-hexyl 339 A F F 340 A c l CI 341 A cl 342 A . F 343 A 344 A -0 345 A -CH - F 346 A -CH2 -125- WO 2007/111864 PCT/US2007/006806 347 A -CH 2 "--a 348 A P OCF 3 349 A Q C3 350 A I CF 3 351 A CI Table 9 F 3 C R Example R 352 \ 355 C 0 -126 - WO 2007/111864 PCT/US2007/006806 356 N F 357 / o N OCF 3 358 359 360 361 o 362 osu CI 363 0 364 F -123657 Pr Pr Cl 366 - 127 - WO 2007/111864 PCT/US2007/006806 367 368 x NEt 2 369 370 0 371 o Pr 372 0o 0 Et Et Table 10 RI R 22 R1' o 0 O N'-OH H Example Isomer R' ,R r R 373 A* H, t-Bu O N - 128- WO 2007/111864 PCT/US2007/006806 374 B* H, t-Bu S 375 A* H, Ph -o 376 B* H, Ph s 377 Me, Me 1_/ OCF 3 378 A* H, t-Bu -o 1 F 379 B* H, t-Bu -o 380 B** H, t-Bu c 381 A** H, t-Bu c 382 A*** H, t-Bu I -- OCF 3 383 B*** H, t-Bu I__ OCF 3 384 B** H, t-Bu -o - 129- WO 2007/111864 PCT/US2007/006806 Table 11 )n R n) 1 0 oo O N" OH H Example n R 385 3 -o 386 1 -o - c 387 1 I\/OCFr 388 1 389 1 390 2 391 2 392 2 cre - 130 - WO 2007/111864 PCT/US2007/006806 Table 12 - R 0 o O N OH H Example n R 393 2 394 2 O OCF, 3 395 2 396 1 397 1c IC or a pharmaceutically acceptable salt or solvate thereof. 19. A pharmaceutical composition comprising a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carrier. 20. A method of treating type 2 diabetes mellitus in a mammalian patient in need of such treatment comprising administering to said patient a compound in accordance with claim 1 in an amount that is effective to treat said type 2 diabetes mellitus. 21. A method of delaying the onset of type 2 diabetes mellitus in a mammalian patient in need thereof, comprising administering to the patient a compound in accordance with claim 1 in an amount that is effective to delay the onset of said type 2 diabetes mellitus. - 131 - WO 2007/111864 PCT/US2007/006806 22. A method of treating hyperglycemia, diabetes or insulin resistance in a mammalian patient in need of such treatment which comprises administering to said patient an effective amount of a compound in accordance with claim 1. 5 23. A method of treating non-insulin dependent diabetes mellitus in a mammalian patient in need of such treatment comprising administering to the patient an anti-diabetic effective amount of a compound in accordance with claim 1. 24. A method of treating obesity in a mammalian patient in need of such treatment D comprising administering to said patient a compound in accordance with claim I in an amount that is effective to treat obesity. 25. A method of treating Syndrome X in a mammalian patient in need of such treatment, comprising administering to said patient a compound in accordance with claim I in an amount 5 that is effective to treat Syndrome X. 26. A method of treating a lipid disorder selected from the group consisting of dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL and high LDL in a mammalian patient in need of such treatment, comprising administering to said patient a compound in D) accordance with claim 1 in an amount that is effective to treat said lipid disorder. 27. A method of treating atherosclerosis in a mammalian patient in need of such treatment, comprising administering to said patient a compound in accordance with claim I in an amount effective to treat atherosclerosis. 5 28. A method of treating a condition selected from the group consisting of: (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low H-IDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis,(14) ) pancreatitis, (15) abdominal obesity, (16) neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19) neuropathy, (20) Syndrome X, and other conditions and disorders where insulin resistance is a component, in a mammalian patient in need of such treatment, comprising administering to the patient a compound in accordance with Claim 1 in an amount that is effective to treat said condition. - 132 -
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